ORCID Profile
0000-0002-7036-1309
Current Organisations
Chittagong Medical College
,
Murdoch University
,
Vanderbilt University School of Medicine
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Publisher: Wiley
Date: 2002
DOI: 10.1046/J.1464-2662.2001.00094.X
Abstract: To estimate the rate of combination antiretroviral treatment change and factors associated with combination antiretroviral treatment change among patients recruited in the Australian HIV Observational Database (AHOD). Analyses were based on patients in the AHOD who had commenced combination antiretroviral treatment after 1 January 1997. Combination antiretroviral treatment change was defined as the addition or change of at least one antiretroviral drug. A random-effect Poisson regression model was used to assess factors associated with increased rates of combination antiretroviral treatment change. A total of 596 patients in the AHOD were included in the analysis, with a median follow-up of 2.3 years. The overall rate of antiretroviral treatment change in this group was 0.45 combinations per year. In a multivariate analysis, a low CD4 count (< 200 cells/microL) at baseline was associated with an increased rate of treatment change [rate ratio (RR)=1.43 95% confidence interval (CI), 1.13, 1.80 P=0.003)]. Combinations including a nonnucleoside reverse transcriptase inhibitor were also associated with slower rates of change than treatment combinations including a protease inhibitor (RR=0.64, 95% CI, 0.51, 0.80, P < 0.001). Initiating combination antiretroviral at a CD4 cell count < 200 cells/microL may be associated with poorer patient outcomes. However, the possibility that clinician or patient concerns about low immunological status led to faster rates of treatment change in this group cannot be discounted.
Publisher: Wiley
Date: 20-11-2022
DOI: 10.1111/TAN.14880
Abstract: Several HLA allelic variants have been associated with protection from or susceptibility to infectious and autoimmune diseases. Here, we examined whether specific HLA alleles would be associated with different Mycobacterium tuberculosis (Mtb) infection outcomes. The HLA alleles present at the ‐A, ‐B, ‐C, ‐DPA1, ‐DPB1, ‐DQA1, ‐DQB1, ‐DRB1, and ‐DRB3/4/5 loci were determined in a cohort of 636 in iduals with known Mtb infection outcomes from South Africa and the United States. Among these in iduals, 203 were QuantiFERON (QFT) negative, and 433 were QFT positive, indicating Mtb exposure. Of these, 99 QFT positive participants either had active tuberculosis (TB) upon enrollment or were diagnosed in the past. We found that DQA1 * 03:01 , DPB1 * 04:02 , and DRB4 * 01:01 were significantly more frequent in in iduals with active TB (susceptibility alleles), as judged by Odds Ratios and associated p‐values, while DPB1 * 105:01 was associated with protection from active TB. Peripheral blood mononuclear cells (PMBCs) from a subset of in iduals were stimulated with Mtb antigens, revealing in iduals who express any of the three susceptibility alleles were associated with lower magnitude of responses. Furthermore, we defined a gene signature associated with in iduals expressing the susceptibility alleles that was characterized by lower expression of APC‐related genes. In summary, we have identified specific HLA alleles associated with susceptibility to active TB and found that the expression of these alleles was associated with a decreased Mtb ‐specific T cell response and a specific gene expression signature. These results will help understand in idual risk factors in progressing to active TB.
Publisher: Wiley
Date: 11-2012
Publisher: Wiley
Date: 04-01-2012
DOI: 10.1111/J.1365-2265.2011.04149.X
Abstract: Vitamin D deficiency (VDD) is prevalent in HIV, and following antiretroviral therapy (ART), increased rates of lipoatrophy and metabolic abnormalities are described. We investigated the relationships between 25-hydroxyvitamin D [25(OH)D] and other metabolic parameters in a group of HIV patients with and without lipoatrophy to examine whether lipoatrophy could explain the high prevalence of VDD and metabolic abnormalities. Vitamin D receptors are expressed in adipose tissue implicating vitamin D, through paracrine/autocrine mechanism, in exerting effects on fat metabolism. HIV patients frequently suffer from VDD, and those treated with thymidine analogues frequently suffer from lipoatrophy so we investigated whether lipoatrophy could explain these associations. Cross-sectional study of HIV-infected male patients (n = 107 39 with lipoatrophy) from the West Australian cohort with measurements of 25(OH)D, adiponectin, insulin, lipids and leg fat as a percentage of mass. Reduced 25(OH)D levels were common and significantly associated with higher serum insulin in the entire cohort (P = 0·006), but there was no difference in 25(OH)D between untreated and antiretroviral-treated patients with or without lipoatrophy. Treated patients with lipoatrophy were more likely to take thymidine analogue therapy, were older and on therapy longer than treated patients without lipoatrophy. Adiponectin levels did not correlate with 25(OH)D, but lipoatrophic-treated patients had lower levels of adiponectin compared with nonlipoatrophic-treated patients. Lower 25(OH)D is associated with higher serum insulin but not lipoatrophy or hypoadiponectinemia in HIV-infected patients. The association between VDD and insulin resistance is likely to be mediated by independent mechanisms.
Publisher: Future Medicine Ltd
Date: 2006
Abstract: There is a growing discussion surrounding the issue of personalized approaches to drug prescription based on an in idual’s genetic makeup. This field of investigation has focused primarily on identifying genetic factors that influence drug metabolism and cellular disposition, thereby contributing to dose-dependent toxicities and/or variable drug efficacy. However, pharmacogenetic approaches have also proved valuable in predicting drug hypersensitivity reactions in selected patient populations, including HIV-infected patients receiving long-term antiretroviral therapy. In this instance, susceptibility has been strongly linked to genetic loci involved in antigen recognition and presentation to the immune system – most notably within the major histocompatibility complex (MHC) region – consistent with the notion that hypersensitivity reactions represent drug-specific immune responses that are largely dose independent. Here the authors describe their experiences with the development of pharmacogenetic approaches to hypersensitivity reactions associated with abacavir and nevirapine, two commonly prescribed antiretroviral drugs. It is demonstrated that prospective screening tests to identify and exclude in iduals with a certain genetic makeup may be largely successful in decreasing or eliminating incidence of these adverse drug reactions in certain populations. This review also explores the broader implications of these findings.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Future Medicine Ltd
Date: 09-2004
Abstract: The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug–host, as well as drug–drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized.
Publisher: Elsevier BV
Date: 2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2008
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477997.V1
Abstract: Supplementary Figure 12: TCRβ repertoires in the post-NAC residual disease or tumor scar are most like PD-1HI CD8+ peripheral repertoires.
Publisher: Elsevier BV
Date: 11-2010
Publisher: Informa Healthcare
Date: 03-2005
Abstract: In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the in idual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.
Publisher: Oxford University Press (OUP)
Date: 11-2003
DOI: 10.1093/QJMED/HCG145
Abstract: The use of HIV protease inhibitors (PIs) as a component of combination antiretroviral therapy in HIV-infected patients has been associated with dyslipidaemia, but its significance as a risk factor for cardiovascular disease is unclear. Endothelial dysfunction is an early phase of atherogenesis that may be assessed non-invasively with ultrasonography in vivo. To evaluate vascular function and investigate potential determinants of endothelial dysfunction of the peripheral circulation in PI-treated, HIV-infected men with dyslipidaemia. Observational, case-control study. We studied 24 HIV-infected, PI-treated men with dyslipidaemia and 24 normolipidaemic, healthy male controls matched for age and body mass index. Brachial artery endothelial function was studied using high-resolution ultrasound and computerized edge-detection software. This non-invasive technique measured post-ischaemic flow-mediated dilatation (FMD), and the endothelium-independent vasodilatory response to glyceryl trinitrate (GTN). Within the HIV patient group, FMD was significantly associated with percentage of 'naïve' CD4 + 45RA + T cells (p = 0.03), while plasma lipid/lipoprotein and insulin levels, body mass, and smoking status did not correlate with endothelial function. FMD was not significantly different between the study group and the controls. The atherogenic potential of PI-associated dyslipidaemia may be attenuated in HIV-infected patients with decreased immune competence, reflecting a possible contribution of cell-mediated immune responses to the pathogenesis of atherosclerosis.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0140-6736(98)26014-4
Abstract: A large body of recent work suggests that neural representations in prefrontal cortex (PFC) are changing over time to adapt to task demands. However, it remains unclear whether and how such dynamic coding schemes depend on the encoded variable and are influenced by anatomical constraints. Using a cued attention task and multivariate classification methods, we show that neuronal ensembles in PFC encode and retain in working memory spatial and color attentional instructions in an anatomically specific manner. Spatial instructions could be decoded both from the frontal eye field (FEF) and the ventrolateral PFC (vlPFC) population, albeit more robustly from FEF, whereas color instructions were decoded more robustly from vlPFC. Decoding spatial and color information from vlPFC activity in the high-dimensional state space indicated stronger dynamics for color, across the cue presentation and memory periods. The change in the color code was largely due to rapid changes in the network state during the transition to the delay period. However, we found that dynamic vlPFC activity contained time-invariant color information within a low-dimensional subspace of neural activity that allowed for stable decoding of color across time. Furthermore, spatial attention influenced decoding of stimuli features profoundly in vlPFC, but less so in visual area V4. Overall, our results suggest that dynamic population coding of attentional instructions within PFC is shaped by anatomical constraints and can coexist with stable subspace coding that allows time-invariant decoding of information about the future target.
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3489447
Publisher: The American Association of Immunologists
Date: 15-04-2010
Abstract: Currently, 1.1 million in iduals in the United States are living with HIV-1 infection. Although this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the United States, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic ersity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes that are determined by the HLA class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically erse national United States cohort of HIV-1–infected in iduals. We found a striking ergence in the immunoselection patterns associated with HLA variants that have very similar or identical peptide-binding specificities but are differentially distributed among racial/ethnic groups. Although their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide-binding groove contribute to race-specific selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the TCR vary significantly within HLA supertype groups, which, in turn, influences HIV-1 evolution.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-05-2002
Abstract: Antigen-specific T cell immunity is HLA-restricted. Human immunodeficiency virus–type 1 (HIV-1) mutations that allow escape from host immune responses may therefore be HLA allele–specific. We analyzed HIV-1 reverse transcriptase sequences from a large HLA- erse population of HIV-1–infected in iduals. Polymorphisms in HIV-1 were most evident at sites of least functional or structural constraint and frequently were associated with particular host HLA class I alleles. Absence of polymorphism was also HLA allele–specific. At a population level, the degree of HLA-associated selection in viral sequence was predictive of viral load. These results support a fundamental role for HLA-restricted immune responses in driving and shaping HIV-1 evolution in vivo.
Publisher: American Society for Microbiology
Date: 15-02-2013
DOI: 10.1128/JVI.02572-12
Abstract: Pol283-8-specific, HLA-B*51:01-restricted, cytotoxic T cells (CTLs) play a critical role in the long-term control of HIV-1 infection. However, these CTLs select for the reverse transcriptase (RT) I135X escape mutation, which may be accumulating in circulating HIV-1 sequences. We investigated the selection of the I135X mutation by CTLs specific for the same epitope but restricted by HLA-B*52:01. We found that Pol283-8-specific, HLA-B*52:01-restricted CTLs were elicited predominantly in chronically HIV-1-infected in iduals. These CTLs had a strong ability to suppress the replication of wild-type HIV-1, though this ability was weaker than that of HLA-B*51:01-restricted CTLs. The crystal structure of the HLA-B*52:01-Pol283-8 peptide complex provided clear evidence that HLA-B*52:01 presents the peptide similarly to HLA-B*51:01, ensuring the cross-presentation of this epitope by both alleles. Population level analyses revealed a strong association of HLA-B*51:01 with the I135T mutant and a relatively weaker association of HLA-B*52:01 with several I135X mutants in both Japanese and predominantly Caucasian cohorts. An in vitro viral suppression assay revealed that the HLA-B*52:01-restricted CTLs failed to suppress the replication of the I135X mutant viruses, indicating the selection of these mutants by the CTLs. These results suggest that the different pattern of I135X mutant selection may have resulted from the difference between these two CTLs in the ability to suppress HIV-1 replication.
Publisher: American Society for Microbiology
Date: 15-09-2008
DOI: 10.1128/JVI.01041-08
Abstract: During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 in iduals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in ∼80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801 P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing in iduals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
Publisher: American Society for Clinical Investigation
Date: 21-05-2018
DOI: 10.1172/JCI121525
Publisher: Springer Science and Business Media LLC
Date: 25-08-2005
Abstract: Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1996
DOI: 10.1097/00002030-199610000-00013
Abstract: To explore trends in cumulative incidence of Kaposi's sarcoma (KS) and the level of immunodeficiency at KS diagnosis among people with AIDS in Australia. Three hospital-based HIV units. Retrospective cohort of 2580 people diagnosed with AIDS over the period 1983-1994, representing 45% of cases of AIDS in Australia over this period. Data including date and CD4 T-lymphocyte count of KS diagnosis was abstracted from medical records. KS occurring as both an initial and subsequent AIDS illness was included. Three subcohorts were defined based on interval of AIDS diagnosis: 1983-1987, 1988-1990, 1991-1994. Cumulative risk estimates for KS development were calculated by the Kaplan-Meier method. KS was diagnosed in 716 people (27.8%), and in 451 (63%) of these as the initial AIDS illness. There was a decline over time in cumulative incidence of KS (P < 0.0005) the cumulative risk of KS at 1 year after AIDS diagnosis declined from 35% for those diagnosed with AIDS during 1983-1987 to 25% for 1991-1994. This decline was not due to a decline in homosexual HIV exposure category, and was independent of CD4 T-lymphocyte count at AIDS. In multivariate analysis independent risk factors for KS development were year of AIDS diagnosis (P = 0.003), male homosexuality (P = 0.003), and CD4 T-lymphocyte count at AIDS greater than 150 x 10(6)/l (P = 0.02). A decline in median CD4 T-lymphocyte count at KS diagnosis was seen, from 67 x 10(6)/l in 1984-1987 to 20 x 10(6)/l for 1991-1994 (P < 0.0005). The decline in incidence and later occurrence of KS suggest several hypotheses, including declining prevalence or reduced virulence of a KS cofactor.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1038/S41598-020-79726-9
Abstract: The self-antigen α-synuclein (α-syn) was recently shown to be associated with Parkinson’s disease (PD). Here we mapped the T cell receptor (TCR) repertoire of α-syn-specific T cells from six PD patients. The self-antigen α-syn-specific repertoire was compared to the repertoire of T cells specific for pertussis (PT), as a representative foreign antigen that most in iduals are exposed to, revealing that the repertoire for α-syn was as erse as the repertoire for PT. The ersity of PT-specific clonotypes was similar between in iduals with PD diagnosis and age-matched healthy controls. We found that the TCR repertoire was specific to each PD patient, and no shared TCRs among patients were defined, likely due to differences in HLA expression that select for different subsets of epitope-specific TCR rearrangements. This study provides the first characterization of α-syn-specific TCR clonotypes in in iduals with PD. Antigen-specific TCRs can serve as immunotherapeutics and diagnostics, and means to track longitudinal changes in specific T cells, and disease progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-05-2009
DOI: 10.1002/HEP.23101
Abstract: Many hepatitis C virus (HCV) infections worldwide are with the genotype 1 and 3 strains of the virus. Cellular immune responses are known to be important in the containment of HCV genotype 1 infection, and many genotype 1 T cell targets (epitopes) that are presented by host human leukocyte antigens (HLAs) have been identified. In contrast, there is almost no information known about the equivalent responses to genotype 3. Immune escape mechanisms used by HCV include the evolution of viral polymorphisms (adaptations) that abrogate this host-viral interaction. Evidence of HCV adaptation to HLA-restricted immune pressure on HCV can be observed at the population level as viral polymorphisms associated with specific HLA types. To evaluate the escape patterns of HCV genotypes 1 and 3, we assessed the associations between viral polymorphisms and specific HLA types from 187 in iduals with genotype 1a and 136 in iduals with genotype 3a infection. We identified 51 HLA-associated viral polymorphisms (32 for genotype 1a and 19 for genotype 3a). Of these putative viral adaptation sites, six fell within previously published epitopes. Only two HLA-associated viral polymorphisms were common to both genotypes. In the remaining sites with HLA-associated polymorphisms, there was either complete conservation or no significant HLA association with viral polymorphism in the alternative genotype. This study also highlights the erse mechanisms by which viral evasion of immune responses may be achieved and the role of genotype variation in these processes. There is little overlap in HLA-associated polymorphisms in the nonstructural proteins of HCV for the two genotypes, implying differences in the cellular immune pressures acting on these viruses and different escape profiles. These findings have implications for future therapeutic strategies to combat HCV infection, including vaccine design.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1992
DOI: 10.1097/00002030-199211000-00009
Abstract: To describe a localized form of Mycobacterium avium intracellulare (MAI) infection occurring concurrently with the restoration of cutaneous delayed-type hypersensitivity (DTH) responses to mycobacterial antigens after commencement of zidovudine therapy in immunodeficient HIV-infected patients. The first 108 Western Australian patients with a CD4+ T-cell count of or = 8 mm and one patient who developed a positive Mantoux test to M. avium purified protein derivative developed an illness characterized by localized MAI infection, lymphadenopathy and/or severe fevers after 1-2 weeks. The development of localized MAI infection and/or fevers shortly after commencing ZDV in immunodeficient HIV-infected patients may reflect restoration of cellular immunity to mycobacterial antigens in some patients rather than early failure of therapy or hypersensitivity to ZDV.
Publisher: BMJ
Date: 18-09-2018
DOI: 10.1136/GUTJNL-2017-313863
Abstract: Helicobacter pylori is the strongest risk factor for gastric cancer however, the majority of infected in iduals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease. Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed. A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034). These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
Publisher: SAGE Publications
Date: 2016
DOI: 10.3851/IMP3056
Publisher: Wiley
Date: 03-10-2023
DOI: 10.1002/LARY.31088
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
Publisher: Elsevier BV
Date: 11-2017
Publisher: Wiley
Date: 17-05-2012
DOI: 10.1038/ICB.2011.34
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0140-6736(05)79021-8
Abstract: Through synaptic connections, long-range circuits transmit information among neurons and connect different brain regions to form functional motifs and execute specific functions. Tracing the synaptic distribution of specific neurons requires submicron-level resolution information. However, it is a great challenge to map the synaptic terminals completely because these fine structures span multiple regions, even in the whole brain. Here, we develop a pipeline including viral tracing, s le embedding, fluorescent micro-optical sectional tomography, and big data processing. We mapped the whole-brain distribution and architecture of long projections of the parvalbumin neurons in the basal forebrain at the synaptic level. These neurons send massive projections to multiple downstream regions with subregional preference. With three-dimensional reconstruction in the targeted areas, we found that synaptic degeneration was inconsistent with the accumulation of amyloid-β plaques but was preferred in memory-related circuits, such as hippoc al formation and thalamus, but not in most hypothalamic nuclei in 8-month-old mice with five familial Alzheimer's disease mutations. Our pipeline provides a platform for generating a whole-brain atlas of cell-type-specific synaptic terminals in the physiological and pathological brain, which can provide an important resource for the study of the organizational logic of specific neural circuits and the circuitry changes in pathological conditions.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-10-2020
Abstract: Robust T cell responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus occur in most in iduals with coronavirus disease 2019 (COVID-19). Several studies have reported that some people who have not been exposed to SARS-CoV-2 have preexisting reactivity to SARS-CoV-2 sequences. The immunological mechanisms underlying this preexisting reactivity are not clear, but previous exposure to widely circulating common cold coronaviruses might be involved. Mateus et al. found that the preexisting reactivity against SARS-CoV-2 comes from memory T cells and that cross-reactive T cells can specifically recognize a SARS-CoV-2 epitope as well as the homologous epitope from a common cold coronavirus. These findings underline the importance of determining the impacts of preexisting immune memory in COVID-19 disease severity. Science , this issue p. 89
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Society for Microbiology
Date: 11-2006
DOI: 10.1128/JVI.00912-06
Abstract: Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 in iduals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.
Publisher: Wiley
Date: 02-1999
DOI: 10.1111/J.1600-065X.1999.TB01398.X
Abstract: An in idual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the erse immunopathological conditions associated with the 8.1 AH.
Publisher: Elsevier BV
Date: 06-1983
DOI: 10.1016/S0022-3468(83)80102-X
Abstract: This preliminary report describes a new method of treating bilateral cryptorchidism that may modify the need for surgical intervention. Four of five boys (3 1/2, 3 1/2, 7, 11 and 12 1/2 years of age) given hourly subcutaneous pulses of luteinizing hormone-releasing hormone (LH-RH, 10 to 100 micrograms/day, given in a 3-min pulse every hour) showed evidence of testicular descent after 3 to 19 weeks. The battery-operated, programmable syringe driver was well tolerated by the boys, and the daily insertion of the scalp-vein needles was managed at home by their parents.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477985.V1
Abstract: Supplementary Figure 16: 8 gene score is predominately expressed by CD8+ T cells and NK cells in both patients.
Publisher: Wiley
Date: 03-10-2007
DOI: 10.1111/J.1445-5994.2007.01477.X
Abstract: Near-perfect adherence to antiretroviral therapy over time is critical to achieve viral suppression and recovery of functional immunity in in iduals infected with HIV. The concept of adherence as a dynamic behaviour influenced by multiple biopsychosocial factors motivated us to implement an integrated, multifactorial programme in our hospital-based setting. The aims of this study were to survey the scope and determinants of non-adherence in patients attending the Ambulatory HIV Service at Royal Perth Hospital, to develop a method for longitudinal monitoring and to implement measures tailored to support in iduals. The US Adult AIDS Clinical Trials Group self-report baseline adherence, follow-up and side-effect questionnaires were used to survey 247 patients at two time-points between September 2002 and February 2003. A longitudinal monitoring method was developed and the WA HIV Cohort Study database used to collate results with clinical markers up to December 2005. Adherence was associated with viral suppression and CD4 T-cell recovery and improved over the 3-year period under observation (all P < 0.001). Diminishing adherence was associated with younger age (P = 0.002), substance use (P < 0.01), perceived stress (P = 0.04) and indicators of depression (P = 0.03). The analyses showed relationships between personal experience of side-effects and the depression indicator scale in patients on antiretroviral therapy. The programme resulted in an improvement in adherence in our cohort even after adjusting for pill burden, dosing frequency and highly active antiretroviral therapy regimen and has enhanced focus on patients vulnerable to non-adherence while supporting those not currently at risk.
Publisher: Public Library of Science (PLoS)
Date: 24-06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2001
DOI: 10.1097/00002030-200107060-00009
Abstract: To determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Analyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients. Average lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P = 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31 z-score per year P < 0.001). Lower initial z-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P = 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P = 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P = 0.04), this effect was abrogated in a multiple linear regression analysis (P = 0.11) with lowest BMI remaining significant (P = 0.04). We found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an in idual's initial z-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spine z-score.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477979.V1
Abstract: Supplementary Figure 2: Pre-NAC sTILs have minimal prognostic value in breast cancer patients with residual disease.
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2022
DOI: 10.1101/2022.02.02.22270308
Abstract: Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Diverse diseases in ergent organ systems are associated with fibrosis, suggesting common biologic mechanisms. One well characterized pathway is chronic inflammation secondary to pathogen. In the present study, we explored the role of the proximal airway microbiome in iSGS pathogenesis. In human s les, abundant bacteria are detectable in iSGS scar as well as in health subglottic controls or patients that developed subglottic stenosis following endotracheal intubation. Interestingly, the community structure of the iSGS proximal airway microbiome does not appear disrupted. Rather, in iSGS defects in the airway epithelial barrier allow displacement of the native microbiome into the immunoprivileged lamina propria and are associated with adaptive immune activation. Animal models of iSGS confirm both bacteria and an adaptive immune response are necessary for pathologic proximal airway fibrosis. Single cell RNA sequencing of the affected airway in iSGS offers an unbiased characterization of the observed epithelial barrier dysfunction. The airway scar in iSGS patients demonstrates basal cell depletion and epithelial acquisition of a mesenchymal phenotype. The epithelial alterations are associated with the observed microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2020
DOI: 10.1101/2020.12.08.416750
Abstract: T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens, and precisely measure virus-specific CD4 + and CD8 + T cells, we studied epitope-specific T cell responses of approximately 100 convalescent COVID-19 cases. The SARS-CoV-2 proteome was probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of HLA alleles for class II responses. For HLA class I, we studied an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identified several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance were observed, which differed for CD4 + T cells, CD8 + T cells, and antibodies. The class I and class II epitopes were combined into new epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4 + and CD8 + T cells.
Publisher: American Society for Microbiology
Date: 07-2004
DOI: 10.1128/JVI.78.13.7069-7078.2004
Abstract: Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8 + T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.
Publisher: Elsevier BV
Date: 08-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2006
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477991.V1
Abstract: Supplementary Figure 14: Differentially expressed genes by cluster in whole blood single cell RNA sequencing.
Publisher: American Society for Microbiology
Date: 04-2014
DOI: 10.1128/JVI.03136-13
Abstract: HIV undergoes high rates of mutation and recombination during reverse transcription, but it is not known whether these events occur independently or are linked mechanistically. Here we used a system of silent marker mutations in HIV and a single round of infection in primary T lymphocytes combined with a high-throughput sequencing and mathematical modeling approach to directly estimate the viral recombination and mutation rates. From million nucleotides (nt) of sequences from HIV infection, we observed 4,801 recombination events and 859 substitution mutations (≈1.51 and 0.12 events per 1,000 nt, respectively). We used experimental controls to account for PCR-induced and transfection-induced recombination and sequencing error. We found that the single-cycle virus-induced mutation rate is 4.6 × 10 −5 mutations per nt after correction. By sorting of our data into recombined and nonrecombined sequences, we found a significantly higher mutation rate in recombined regions ( P = 0.003 by Fisher's exact test). We used a permutation approach to eliminate a number of potential confounding factors and confirm that mutation occurs around the site of recombination and is not simply colocated in the genome. By comparing mutation rates in recombined and nonrecombined regions, we found that recombination-associated mutations account for 15 to 20% of all mutations occurring during reverse transcription.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 09-04-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1994
DOI: 10.1097/00002030-199409000-00007
Abstract: To test the hypothesis that subclinical Mycobacterium avium intracellulare complex (MAC) infection may result in the development of a tuberculin response in immunodeficient HIV-infected in iduals treated with zidovudine. Longitudinal, observational study. The Western Australian HIV Cohort Study a prospective, single centre, population-based observational study of the natural history of HIV disease. Forty-nine patients with impaired delayed-type hypersensitivity (DTH) responses and negative tuberculin responses in whom DTH responses were augmented within 6 months of starting zidovudine therapy. Progression to disseminated MAC infection stratified according to the presence or absence of a tuberculin response in the first 6 months of zidovudine therapy. Twenty-nine of the patients developed a post-zidovudine tuberculin response. None of the tuberculin non-responders developed disseminated MAC infection during the study period the Kaplan-Meier probability estimate of disseminated MAC infection was 50% at 24 months and reached 100% 40 months after zidovudine was commenced in tuberculin responders. All patients with disseminated MAC infection had become anergic to all antigens, including tuberculin, before diagnosis. The probability of a post-zidovudine tuberculin response was related to the severity of peripheral blood CD4+ T-cell depletion, rising from an estimated 20% at 20% CD4+ T cells to 100% at < or = 1% CD4+ T cells. The restoration of a cellular immune response against subclinical MAC infection can be demonstrated by measuring the DTH response to tuberculin in patients with impaired DTH augmented by zidovudine therapy. The findings suggest that MAC infection is almost inevitable, but often asymptomatic, in profoundly immunodeficient HIV-infected patients and that a prolonged subclinical phase of MAC infection is usual.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-06-2005
DOI: 10.1097/01.AIDS.0000171414.99409.FB
Abstract: A patch test (PT) may be useful in defining true abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2014
Publisher: Springer Science and Business Media LLC
Date: 22-07-2019
Publisher: Wiley
Date: 16-05-2005
DOI: 10.1111/J.1399-0039.2005.00401.X
Abstract: Susceptibility to abacavir hypersensitivity (ABC HSR) is strongly associated with alleles carried on the 57.1 ancestral haplotype including HLA-B*5701 and Hsp70 Hom M493T. In one study, prospective testing for HLA-B*5701 and exclusion of in iduals carrying this allele, from receiving abacavir, substantially lowered the incidence of ABC HSR to 0% (95% confidence interval 0-0.075%). The presence of HLA-B*5701 is usually detected by standard serological tests and by molecular genetic methods such as sequence-based typing (SBT). While the former test cannot discriminate between HLA-B57 subtypes, the expensive SBT may not be readily available in all laboratories. Hence, an alternate method was developed to detect HLA-B*5701 using allele and group-specific polymerase chain reaction-sequence-specific primers (PCR-SSP) typing. This PCR-SSP-typing method positively lified all HLA-B*5701 alleles in concordance with their SBT-assigned typing. This multiplexed SSP assay was able to distinguish between HLA-B*5701 (n = 10) and closely related HLA-B57 alleles B*5702 (n = 2), -B*5703 (n = 1), -B*5704 (n = 1) alleles and non-HLA-B*57 alleles (n = 61). In conclusion, this method of HLA-B*5701 detection is a rapid and accurate typing method with high specificity, sensitivity and reproducibility.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2019
DOI: 10.1038/S41467-019-11396-2
Abstract: Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug henotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
Publisher: American Society for Microbiology
Date: 12-2015
DOI: 10.1128/IAI.00918-15
Abstract: Helicobacter pylori exhibits a high level of intraspecies genetic ersity. In this study, we investigated whether the ersification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori ersification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur ( fur-R88H ). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori -infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment.
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2020
DOI: 10.1101/2020.07.29.227082
Abstract: Infections with varicella zoster virus (VZV), a member of the Herpesviridae family, are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox, and due to the virus’s capacity to remain latent in neurons, it can reactivate later in life causing herpes zoster (HZ), also known as shingles. Two different vaccines have been developed to prevent HZ, one based on a live attenuated VZV strain (Zostavax) and the other on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (80 years of age and beyond). In this context, it is of much interest to understand if there is a role for T cell immunity in differential clinical outcome, and if there is a correlate of protection between T cell immunity and Shingrix efficacy. In this study, we characterized Shingrix specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets non-structural proteins (NS), while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule transfected lines, we experimentally determined HLA restrictions for 94 different donor eptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of responding subjects. Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize specificity, magnitude and phenotype of VZV specific T cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-02-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-09-2017
Publisher: Cold Spring Harbor Laboratory
Date: 07-2020
DOI: 10.1101/2020.07.01.181867
Abstract: We have developed periscope, a tool for the detection and quantification of sub-genomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed “sub-genomic RNAs”. sgRNAs are produced through discontinuous transcription which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L which is located in the 5’ UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5’ end of all sgRNA. We applied periscope to 1,155 SARS-CoV-2 genomes from Sheffield, UK and validated our findings using orthogonal datasets and in vitro cell systems. Using a simple local alignment to detect reads which contain the leader sequence we were able to identify and quantify reads arising from canonical and non-canonical sgRNA. We were able to detect all canonical sgRNAs at expected abundances, with the exception of ORF10. A number of recurrent non-canonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2+/− cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing datasets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 s les worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.
Publisher: American Society for Microbiology
Date: 23-11-2020
DOI: 10.1128/JVI.01641-20
Abstract: Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying the patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize the specificity, magnitude, and phenotype of VZV-specific T cells.
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.COI.2006.05.015
Abstract: Viruses are prototypic obligate intracellular pathogens, and are therefore, by necessity, highly pre-adapted to surviving the host immune response. Nevertheless, host genetic factors remain an important determinant of disease outcome, particularly in the case of viruses that have encountered humans in the more recent past (e.g. human immunodeficiency virus). Recent studies have identified an increasingly rich network of functionally relevant polymorphic immune factors, including major MHC alleles, killer immunoglobulin-like receptors and functional chemokine receptor polymorphisms. Moreover, genetic variation is increasingly appreciated beyond the single genotype level, incorporating extended haplotypes as well as regions of segmental genetic duplication. These issues can be considered within an evolutionary perspective that acknowledges the crucial role of adaptive host-viral relationships in shaping both host and pathogen genetic ersity.
Publisher: AMPCo
Date: 11-1992
DOI: 10.5694/J.1326-5377.1992.TB137397.X
Abstract: To determine the incidence and nature of occupational exposures to blood and body fluids in health care workers. 332 reports of occupational exposure were analysed and are presented. A major teaching hospital. All staff at Royal Perth Hospital who reported an occupational exposure to blood or body fluids to the Department of Clinical Immunology between 1 January 1990 and 31 August 1991. The rate of reported occupational exposure according to staff category, nature of exposure, HIV status of source patient, activity at the time of exposure and compliance with infection control measures. 332 reports from 323 health care workers were received, giving an overall incidence of 6.1 per 100 full time equivalent (FTE) years. Nursing staff (9.4/100 FTE years) and medical staff (9.0/100 FTE years) reported exposure more frequently than housekeeping staff (2.5/100 FTE years) or paramedical staff (2.3/100 FTE years) (P < 0.001). The rate of exposure to HIV antibody positive patients was only 0.24/100 FTE years. Needlestick or other blood contaminated sharps injuries accounted for 83.4% (277/332) of reports and failure to observe universal precautions for 34.0% of reports. Insertion and operation of parenteral lines (24%) and performing operations (15.4%) were the activities most often associated with occupational exposure. No occupationally acquired infections were observed. Despite the immediate availability of zidovudine, acceptance by health care workers with high risk occupational exposure was low (18.8%). Occupational exposure to blood and body fluids is common among health care workers but most exposures confer a low risk of blood borne infection. The introduction of an occupational exposure assessment program has many benefits, including optimal management of injuries and acquisition of data on infection control measures, and may protect health care institutions from false claims for compensation.
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478000.V1
Abstract: Supplementary Figure 11: Cytokine secretion is markedly enriched in PD-1HI T cells after NAC in a patient with pCR to NAC in TNBC.
Publisher: Oxford University Press (OUP)
Date: 07-2006
DOI: 10.1086/504874
Abstract: Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive in iduals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.
Publisher: Elsevier BV
Date: 1981
DOI: 10.1016/S0140-6736(81)90724-8
Abstract: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have key differences in clinical presentation, radiographic findings, comorbidities and pathogenesis to distinguish between these common forms of chronic inflammatory arthritis. Joint involvement is typically, but not always, asymmetric in PsA, while it is predominantly symmetric in RA. Bone erosions, without new bone growth, and cervical spine involvement are distinctive of RA, while axial spine involvement, psoriasis and nail dystrophy are distinctive of PsA. Patients with PsA typically have seronegative test findings for rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibodies, while approximately 80% of patients with RA have positive findings for RF and CCP antibodies. Although there is overlap in the pathogenesis of PsA and RA, differences are also present that affect the efficacy of treatment. In PsA, levels of interleukin (IL)-1β, IL-6, IL-17, IL-22, IL-23, interferon-γ and tumour necrosis factor-α (TNF-α) are elevated, and in RA, levels of IL-1, IL-6, IL-22, IL-33, TNF-α, chemokine ligand 11 and chemokine C-X-C motif ligand 13 are elevated. Differences in the pathogenesis of RA and PsA translate into some variances in the specificity and efficacy of therapies.
Publisher: Frontiers Media SA
Date: 05-07-2019
Publisher: The American Association of Immunologists
Date: 04-2006
DOI: 10.4049/JIMMUNOL.176.7.4094
Abstract: Immunodominance is variably used to describe either the most frequently detectable response among tested in iduals or the strongest response within a single in idual, yet factors determining either inter- or intrain idual immunodominance are still poorly understood. More than 90 in iduals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intrain idual immunodominance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1995
Publisher: Oxford University Press (OUP)
Date: 15-06-2008
DOI: 10.1086/588479
Abstract: We assessed the influence of human leukocyte antigen (HLA) alleles HLA-Bw4 and HLA-Bw6 on CD4 T cell recovery after starting successful combination antiretroviral therapy in 265 in iduals. The median gains in the CD4 T cell count after 4 years were 258 cells/microL for HLA-Bw4 homozygotes, 321 cells/microL for HLA-Bw4/Bw6 heterozygotes, and 363 cells/microL for HLA-Bw6 homozygotes (P = .01, compared with HLA-Bw4 homozygotes). HLA-Bw4 homozygosity appears to predict an impaired CD4 T cell recovery after initiation of combination antiretroviral therapy.
Publisher: Wiley
Date: 30-01-2016
DOI: 10.1111/TID.12470
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477958
Abstract: Supplementary Figure 9: Changes in sTILs after NAC do not correspond to an observed change in T cell clonality.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2004
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477958.V1
Abstract: Supplementary Figure 9: Changes in sTILs after NAC do not correspond to an observed change in T cell clonality.
Publisher: Elsevier BV
Date: 02-2016
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-03-2007
Abstract: Escape from T cell–mediated immune responses affects the ongoing evolution of rapidly evolving viruses such as HIV. By applying statistical approaches that account for phylogenetic relationships among viral sequences, we show that viral lineage effects rather than immune escape often explain apparent human leukocyte antigen (HLA)–mediated immune-escape mutations defined by older analysis methods. Phylogenetically informed methods identified immune-susceptible locations with greatly improved accuracy, and the associations we identified with these methods were experimentally validated. This approach has practical implications for understanding the impact of host immunity on pathogen evolution and for defining relevant variants for inclusion in vaccine antigens.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.IMMUNI.2008.04.020
Abstract: The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S0140-6736(02)07873-X
Abstract: The use of abacavir--a potent HIV-1 nucleoside-analogue reverse-transcriptase inhibitor--is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1-positive in iduals treated with abacavir. MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 in iduals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 in iduals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (p(c)) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined. HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29-481], p(c)<0.0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20-268], p(c)<0.0001 ). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43-15 675], p(c)<0.0001). Other MHC markers also present on the 57.1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. Genetic susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient.
Publisher: American Society for Microbiology
Date: 15-08-2007
DOI: 10.1128/JVI.02740-06
Publisher: American Society for Microbiology
Date: 15-09-2006
DOI: 10.1128/JVI.00888-06
Abstract: APOBEC3G and APOBEC3F restrict human immunodeficiency virus type 1 (HIV-1) replication in vitro through the induction of G→A hypermutation however, the relevance of this host antiviral strategy to clinical HIV-1 is currently not known. Here, we describe a population level analysis of HIV-1 hypermutation in near-full-length clade B proviral DNA sequences ( n = 127). G→A hypermutation conforming to expected APOBEC3G polynucleotide sequence preferences was inferred in 9.4% ( n = 12) of the HIV-1 sequences, with a further 2.4% ( n = 3) conforming to APOBEC3F, and was independently associated with reduced pretreatment viremia (reduction of 0.7 log 10 copies/ml P = 0.001). Defective vif was strongly associated with HIV-1 hypermutation, with additional evidence for a contribution of vif amino acid polymorphism at residues important for APOBEC3G- vif interactions. A concurrent analysis of APOBEC3G polymorphism revealed this gene to be highly conserved at the amino acid level, although an intronic allele (6,892 C) was marginally associated with HIV-1 hypermutation. These data indicate that APOBEC3G-induced HIV-1 hypermutation represents a potent host antiviral factor in vivo and that the APOBEC3G- vif interaction may represent a valuable therapeutic target.
Publisher: American Diabetes Association
Date: 04-09-2018
DOI: 10.2337/DB18-0040
Abstract: Adipose tissue (AT) CD4+ and CD8+ T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8+ and CD4+ TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8+ T cells, HFD reduced TCR ersity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8+ T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice isoLGs were elevated in M2-polarized macrophages, promoting CD8+ T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477970.V1
Abstract: Supplementary Figure 5: The change in sTILs during NAC is not prognostic for outcome in TNBC patients with residual disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2001
DOI: 10.1097/00002030-200104130-00007
Abstract: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1998
DOI: 10.1097/00042560-199801001-00008
Abstract: The efficacy of primary prophylactic treatment for opportunistic infections can be estimated in an observational cohort study by adjusting for clinical and laboratory markers of the immunodeficiency (e.g., oral candidiasis, CD4%, lymphocyte cell counts) as time-dependent co-variates (providing that the treatment does not directly alter the markers). However, the CD4 cell count provides an incomplete measure of the protective immune response, and the efficacy of treatment may be underestimated if there is inadequate adjustment for the severity of immunodeficiency. Unlike prophylactic therapies, the efficacy of which remains relatively constant over time, antiretroviral therapy may produce only transient or time-limited benefits. This problem can be minimized by allowing the effect of antiretroviral therapy to vary over time in Cox proportional hazards models (i.e., to allow the antiretroviral therapy coefficient to change over time). Another difficulty is that CD4 cell counts may underestimate the degree of immunodeficiency after prolonged zidovudine (AZT) monotherapy. If post-antiretroviral therapy CD4 cell counts are used to adjust for the stage of immunodeficiency, it may therefore be helpful to adjust for the duration of antiretroviral therapy with the CD4 cell count at the time of starting antiretroviral therapy. It is interesting to consider statistical models of progressive HIV-induced immunodeficiency in the context of the evolution of host immunity. HIV infection results in the loss of the relatively recently evolved adaptive CD4 T cell-mediated immunity to intracellular parasites. The infected host may compensate for this by making greater use of phylogenetically ancient, more innate protective responses. Because these compensatory responses are polymorphic, this results in the appearance of differences between in iduals in the immune response to HIV as the disease progresses. Data from the Western Australia HIV Cohort Study support a two-stage model of immunopathology. The first stage of this model involves a loss of mucosal immunity and occurs at a variable CD4 cell count (of between 400 cells/mm3 and zero), and is marked by a loss of cutaneous delayed-type hypersensitivity responses and oral candidiasis, seborrheic dermatitis, and Pneumocystis carinii pneumonia. The second stage of the model involves a loss of systemic immunity and requires profound CD4 T-cell lymphopenia (CD4 cell count <50 cells/mm3), and is marked by infections such as cytomegalovirus and disseminated Mycobacterium avium infection. The influence of HLA type on the risk for such opportunistic infections becomes apparent during this late phase.
Publisher: Elsevier BV
Date: 10-2008
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.GENE.2010.08.009
Abstract: Measurements of population ersity are fundamental to the reconstruction of the evolutionary and epidemiological history of organisms. Commonly used protocols to measure population ersity using the polymerase chain reaction (PCR) are prone to the introduction of artificial chimeras. These are often difficult to detect and can confound the correct interpretation of results due to the false generation of recombinants when the underlying DNA s le contains multiple distinct templates. This study presents a standardised procedure to suppress the formation of artificial chimeras during PCR lification. The solution is based on the accurate determination of the efficiency and end point of the log-linear phase of a PCR. This procedure will facilitate the generation of data sets that more accurately reflect the underlying population ersity rather than artifacts introduced by the process itself.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478012
Abstract: Dataset 2: Metadata and clonotype data for TCRβ sequencing (Archer) in 4 patients (peripheral CD8+ PD-1HI and CD8+ PD-1NEG T cells and post-NAC tumor), before (n=3) and after (n=4) NAC.
Publisher: Wiley
Date: 04-2000
DOI: 10.1046/J.1468-1293.2000.00012.X
Abstract: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log10 copies/mL). Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients. Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses. We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.
Publisher: Public Library of Science (PLoS)
Date: 16-02-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478003.V1
Abstract: Supplementary Figure 10: Ex le FACS gating to identify PD-1HI CD8+ T cells from peripheral blood.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529814
Abstract: AbstractPurpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME). Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1 sup HI /sup ) CD8 sup + /sup peripheral T cells and examination of a cytolytic gene signature in whole blood. Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden. Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478015
Abstract: Dataset 1: Metadata and clonotype data for TCRβ sequencing (Adaptive) in 15 pairs of NAC-treated patients (tumor data).
Publisher: Elsevier BV
Date: 08-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477961
Abstract: Supplementary Figure 8: Changes in immune-related genes in response to NAC are not associated with outcome in ER+ or HER2+ tumors with residual disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477964.V1
Abstract: Supplementary Figure 7: Changes in immunologic signatures in response to NAC are not associated with outcome in non-TNBC tumors with residual disease.
Publisher: Public Library of Science (PLoS)
Date: 20-02-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477964
Abstract: Supplementary Figure 7: Changes in immunologic signatures in response to NAC are not associated with outcome in non-TNBC tumors with residual disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478018
Abstract: Supplementary Tables
Publisher: American Society for Microbiology
Date: 15-10-2005
DOI: 10.1128/JVI.79.20.12952-12960.2005
Abstract: Human immunodeficiency virus type 1 (HIV-1) evades CD8 + T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8 + T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8 + T-cell responses and autologous viral sequences in an HIV-1-infected in idual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8 + T cells, four of which underwent mutation associated with dramatic loss of the original CD8 + response. However, following the G 357 S escape in the HLA-A11-restricted Gag 349-359 epitope and the decline of wild-type-specific CD8 + T-cell responses, a novel CD8 + T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8 + T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vβ repertoire. Additional studies of chronically HIV-1-infected in iduals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G 357 S escape variant of the Gag 349-359 epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8 + T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8 + T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants.
Publisher: Elsevier
Date: 2012
Publisher: American Society for Microbiology
Date: 05-2014
DOI: 10.1128/JVI.03303-13
Abstract: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11 Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a -log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a -log-higher viral load ( P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of ,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a -log increase in viral load in HLA-B*57:03-positive subjects ( P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.
Publisher: Elsevier BV
Date: 12-2020
Publisher: JSTOR
Date: 08-1995
DOI: 10.2307/1403613
Publisher: Wiley
Date: 13-04-2022
DOI: 10.1111/IRV.12982
Abstract: The Omicron variant of SARS‐CoV‐2 achieved worldwide dominance in late 2021. Early work suggests that infections caused by the Omicron variant may be less severe than those caused by the Delta variant. We sought to compare clinical outcomes of infections caused by these two strains, confirmed by whole genome sequencing, over a short period of time, from respiratory s les collected from SARS‐CoV‐2 positive patients at a large medical center. We found that infections caused by the Omicron variant caused significantly less morbidity, including admission to the hospital and requirement for oxygen supplementation, and significantly less mortality than those caused by the Delta variant.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2005
DOI: 10.1038/NI1281
Abstract: Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.
Publisher: Elsevier BV
Date: 2014
Publisher: American College of Physicians
Date: 06-11-2001
DOI: 10.7326/0003-4819-135-9-200111060-00008
Abstract: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. To examine postulated associations of genetic alleles with HIV-1 disease progression. Meta-analysis of in idual-patient data. 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. Patients with HIV-1 infection who were of European or African descent. Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74 P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL P 0.5 for all). The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.
Publisher: American Society for Microbiology
Date: 04-2009
DOI: 10.1128/JVI.02459-08
Abstract: Elite controllers (EC) of human immunodeficiency virus type 1 (HIV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8 + T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag , pol , and nef sequences from HLA- erse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC, compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HIV-1 infection.
Publisher: Wiley
Date: 16-04-2019
DOI: 10.1002/MGG3.686
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2016
DOI: 10.1158/1078-0432.CCR-15-1125
Abstract: Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1–targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras–MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras–MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1–targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res 22(6) 1499–509. ©2015 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478000
Abstract: Supplementary Figure 11: Cytokine secretion is markedly enriched in PD-1HI T cells after NAC in a patient with pCR to NAC in TNBC.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.HUMIMM.2018.01.004
Abstract: DNA sequence-based typing at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci was performed on s les provided by 159 in iduals from the Worcester region of the Western Cape province of South Africa. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, and -DRB1 loci. A minor deviation was detected at the HLA-DQB1 locus due to an excess of homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3425.
Publisher: American Society for Microbiology
Date: 15-12-2012
DOI: 10.1128/JVI.01998-12
Abstract: HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by in idual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected in iduals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2020
DOI: 10.1158/1078-0432.CCR-19-3685
Abstract: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME). We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood. In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden. We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
Abstract: Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV‐negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross‐sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV‐related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P .0001). Higher mean corCSA was present in those with coronary artery calcium ( P =0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P =0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4 + T‐cell count (ρ=−0.2, P =0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P =0.08 to ρ=0.3, P =0.01). CorCSA was also inversely correlated with plasma IL‐10 (ρ=−0.25, P =0.03) but had no relationship with IL‐6 (ρ=0.11, P =0.4) or IL‐1β (ρ=0.08, P =0.5). Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T‐cell count, lower circulating IL‐10, and possibly a longer antiretroviral therapy duration in persons with HIV. Clinicaltrials.gov Unique identifier: NCT04451980.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2017
DOI: 10.1038/S41598-017-08876-0
Abstract: Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01 . An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478003
Abstract: Supplementary Figure 10: Ex le FACS gating to identify PD-1HI CD8+ T cells from peripheral blood.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478009
Abstract: Supplementary Legends
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2019
DOI: 10.1101/753806
Abstract: Pulmonary fibrosis is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix. In order to comprehensively define the cell types, mechanisms and mediators driving fibrotic remodeling in lungs with pulmonary fibrosis, we performed single-cell RNA-sequencing of single-cell suspensions from 10 non-fibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell types. We report a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF, and identify several previously unrecognized epithelial cell phenotypes including a KRT5 − / KRT17 + , pathologic ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially-discrete manner. Together these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease, and indicate a ersity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis. Single-cell RNA-sequencing provides new insights into pathologic epithelial and mesenchymal remodeling in the human lung.
Publisher: Public Library of Science (PLoS)
Date: 29-05-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478006
Abstract: Supplementary Figure 1: Representative images of high and low sTILs.
Publisher: Massachusetts Medical Society
Date: 20-11-2003
DOI: 10.1056/NEJMOA030218
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
DOI: 10.1038/S41598-018-25559-6
Abstract: Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8 + T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4 + T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4 + T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01 Fisher’s exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4 + T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4 + T cell epitopes.
Publisher: Annual Reviews
Date: 06-01-2019
DOI: 10.1146/ANNUREV-PHARMTOX-010818-021818
Abstract: Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell–mediated ADRs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478009.V1
Abstract: Supplementary Legends
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477979
Abstract: Supplementary Figure 2: Pre-NAC sTILs have minimal prognostic value in breast cancer patients with residual disease.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Springer Science and Business Media LLC
Date: 17-11-2016
DOI: 10.1038/GENE.2016.42
Publisher: CSIRO Publishing
Date: 2005
DOI: 10.1071/SH04058
Abstract: Lipoatrophy is perhaps the most visibly recognisable component of antiretroviral-therapy-associated lipodystrophy due to the rarity of this form of body composition change in the general population. In this respect, it is apparent that lipoatrophy represents a form of drug toxicity specifically involving the subcutaneous fat tissue, resulting in pathological fat loss that preferentially affects the limbs and face. It is now clear that the choice and duration of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy (stavudine zidovudine) is the dominant risk factor for clinical lipoatrophy, as well as for the pathological changes to adipose tissue that underlie the clinical syndrome. Host factors have also emerged as important modulators of lipoatrophy severity in patients receiving these NRTI drugs, including age, racial origin, and severity of immune deficiency. On the other hand, the use of selected HIV protease inhibitor drugs is more closely associated with metabolic complications such as dyslipidemia and insulin resistance and has not been convincingly linked to lipoatrophy. This review examines the clinical and pathological manifestations of lipoatrophy, and also presents information regarding the safety profile of alternative NRTI drugs, such as tenofovir and abacavir, that have not been associated with lipoatrophy risk. With increasing knowledge of lipoatrophy pathogenesis, it is likely that moderate and severe forms of this complication can now be considered a preventable complication of HIV treatment. However, it is also important to recognise that there is an ongoing burden of disease in patients who have been affected by lipoatrophy over the past six years, and that therapeutic management of established lipoatrophy will remain a challenge into the future.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-07-2020
Abstract: Single-cell RNA sequencing provides new insights into pathologic epithelial and mesenchymal remodeling in the human lung.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2022
DOI: 10.1038/S42003-022-03058-9
Abstract: Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.
Publisher: Wiley
Date: 26-07-2016
DOI: 10.1111/CEA.12772
Publisher: Elsevier BV
Date: 05-2009
Publisher: eLife Sciences Publications, Ltd
Date: 02-10-2018
DOI: 10.7554/ELIFE.39140
Abstract: Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified an interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in a partially SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.
Publisher: Massachusetts Medical Society
Date: 18-08-2011
DOI: 10.1056/NEJMC1105467
Publisher: Springer Science and Business Media LLC
Date: 03-04-2001
DOI: 10.1007/PL00011252
Abstract: Reported here is a case of cerebral Mycobacterium avium complex infection that occurred in an HIV-infected patient, who had been treated for disseminated infection and had discontinued clarithromycin and ethambutol following a significant rise in his CD4+ T-cell count after starting highly active antiretroviral therapy. He responded well to excision of the lesion and reinstitution of multidrug therapy. Caution should be exercised when considering ceasing maintenance therapy for disseminated Mycobacterium avium complex infection in HIV-infected patients who demonstrate an apparently good immunologic response to highly active antiretroviral therapy, as this response may not necessarily restore protective immunity against all opportunistic pathogens.
Publisher: Wiley
Date: 2003
DOI: 10.1002/SIM.1325
Abstract: The introduction of potent antiretroviral therapies for treatment of HIV infection typically results in a dramatic reduction in plasma HIV RNA concentration, often to levels undetectable by current measurement practices. However, although a high proportion of patients achieve 'undetectability', many then experience a return to a state of detectability at a later date. As evaluation of virologic response provides a useful measure of therapy efficacy, it is of interest to estimate the proportions of cases with undetectable viral load over time following commencement of treatment. These proportions depend on the rates of transition from detectability to undetectability and subsequent return to detectability, and may be related to covariates or risk factors, possibly differing in both transitions. We consider construction of detectability profiles as estimates of these proportions, based on parametric modelling of the component survival distributions. The method is applied to an examination of the effects of baseline CD4 T-cell lymphocyte counts on virologic response to therapy amongst patients of the Western Australian HIV Cohort Study.
Publisher: Proceedings of the National Academy of Sciences
Date: 15-03-2004
Abstract: Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B * 5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed in iduals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B * 5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960 P 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom ( HspA1L , resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B * 5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893 P 0.00001). In iduals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8 + T cell depletion. These data indicate that the concurrence of HLA-B * 5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B * 5701 -restricted immune response to abacavir.
Publisher: Elsevier BV
Date: 06-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478015.V1
Abstract: Dataset 1: Metadata and clonotype data for TCRβ sequencing (Adaptive) in 15 pairs of NAC-treated patients (tumor data).
Publisher: Elsevier BV
Date: 03-2011
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477982
Abstract: Supplementary Figure 17: An 8-gene activated T cell signature derived from whole blood at surgery is associated with residual disease burden and recurrence.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2022
Abstract: In a longitudinal, prospective cohort study, we observed that patients with PR3-ANCA vasculitis and HLA-DPB1*04:01 are more likely to experience disease flares, which informed our hypothesis that HLA has an immunopathogenic role. We found that an epitope of PR3 (PR3 225-239 ) has high affinity for HLA-DPB1*04:01. By examining patient peripheral blood mononuclear cells, we demonstrated that PR3 225-239 presentation by HLA-DPB1*04:01 stimulates PR3 225-239 –specific autoreactive T cells. This may explain the associated increased relapse risk. However, in patients who are in long-term remission off therapy, HLA-DPB1 + cells bind PR3 225-239 at levels seen in healthy controls. The diminished interaction between HLA-DPB1 and autoantigen in long-term remission signals immunological nonresponsiveness, creating a foundation to define immunological remission. PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3 225–239 ). Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA eptide multimers) identified autoreactive T cells in vitro. The HLA-DPB1*04:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06 95% CI, 1.01 to 4.20) but not in myeloperoxidase (MPO)-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3 225–239 ) and HLA-DPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3 225–239 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers. The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3 225–239 initiate an immune response. Autoreactive T cells specifically recognized PR3 225–239 presented by HLA-DPB1*04:01. Although larger studies should validate these findings, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunologic nonresponsiveness.
Publisher: Future Medicine Ltd
Date: 07-2009
DOI: 10.2217/PME.09.12
Abstract: The concept of personalizing antiretroviral therapy is not novel, since the complexity of the HIV patient and their therapy has always demanded consideration of the patient’s ‘pharmacoecology’, taking into account factors such as adherence, drug–drug and food–drug interactions, underlying disease and host states, such as organ dysfunction and pregnancy. Recent advances in science have taken this one step further with the technology now available to use both a candidate and whole-genome approach to explore the genetics of host–virus interactions, as well as the pharmacogenetics of the toxicity and efficacy of antiretroviral therapy. The genetics of host–virus interactions have improved our understanding of the pathogenesis of HIV which will aid in the research and development of an HIV vaccine. Most published HIV pharmacogenetic studies have utilized a candidate gene approach. Although these types of studies have provided insight into the pathogenesis and pharmacogenetics of drug disposition, drug interactions, drug efficacy and toxicity and host–virus interactions, very few will lend themselves to a widespread clinical application. The application of HLA-B*5701 screening to prevent abacavir hypersensitivity acts as an important ex le of the successful widespread implementation of a pharmacogenetic test into the clinic and defines the key steps necessary for the clinical application of pharmacogenetic tests in general.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477985
Abstract: Supplementary Figure 16: 8 gene score is predominately expressed by CD8+ T cells and NK cells in both patients.
Publisher: SAGE Publications
Date: 05-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477967
Abstract: Supplementary Figure 6: Neither time of s le nor institution drive significant gene expression changes.
Publisher: Wiley
Date: 05-2007
DOI: 10.1111/J.1399-0039.2007.00840.X
Abstract: Inheritance of HLA-B*5701 is a strong predictor of a hypersensitivity reaction to the anti-HIV drug abacavir. The identification of susceptible in iduals prior to the institution of abacavir therapy is therefore of clinical importance and has generated demand for a simple and rapid diagnostic test for carriage of HLA-B*5701. In this study, we describe the development of such a method based on allele-specific polymerase chain reaction (AS-PCR) and melting curve analysis. Ninety-six patient s les including 36 HLA-B*5701-positive s les and 60 HLA-B*5701-negative s les were analysed. Compared with sequence-based typing, this method had 100% sensitivity and specificity for the HLA-B*5701 allele. In conclusion, the AS-PCR/melting curve approach minimises post-polymerase chain reaction handling processing and provides an attractive alternative to currently described AS-PCR methods.
Publisher: AMPCo
Date: 07-1992
Publisher: SAGE Publications
Date: 10-2009
DOI: 10.3851/IMP1419
Abstract: All site-specific interactions between HIV type-1 (HIV-1) subtype, human leukocyte antigen (HLA)-associated immune selection and integrase inhibitor resistance are not completely understood. We examined naturally occurring polymorphisms in HIV-1-integrase sequences from 342 antiretroviral-naive in iduals from the Western Australian HIV Cohort Study and the Swiss HIV Cohort Study. Standard bulk sequencing and sequence-based typing were used to generate integrase sequences and high-resolution HLA genotypes, respectively. Viral residues were examined with respect to drug resistance mutations and CD8 + T-cell escape mutations. In both predominantly subtype B cohorts, 12 of 38 sites that mediate integrase inhibitor resistance mutations were absolutely conserved, and these included the primary resistance mutations. There were 18 codons with non-primary drug resistance-associated substitutions at rates of up to 58.8% and eight sites with alternative polymorphisms. Five viral residues were potentially subject to dual-drug and HLA-associated immune selection in which both selective pressures either drove the same amino acid substitution (codons 72, 157 and 163) or HLA alleles were associated with an alternative polymorphism that would alter the genetic barrier to resistance (codons 125 and 193). The common polymorphism T125A, which was characteristic of non-subtype B and was also associated with carriage of HLA-B*57/*5801, increased the mutational barrier to the resistance mutation T125K. Primary integrase inhibitor resistance mutations were not detected in the absence of drug exposure in keeping with sites of high constraint. Viral polymorphisms caused by immune selection and/or associated with non-subtype B might alter the genetic barrier to some non-primary resistance-associated mutations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-03-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 22-07-2013
Abstract: Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term “targeting efficiency,” and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009–2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses ( P = 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality ( r = 0.37, P = 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations.
Publisher: American Society for Microbiology
Date: 13-07-2022
DOI: 10.1128/JVI.00122-22
Abstract: The integration of human immunodeficiency virus type 1 (HIV-1) into chromosomal DNA establishes the long-term persistence of HIV-1 as proviruses despite effective antiretroviral therapy (ART). Characterizing proviruses is difficult because of their rarity in in iduals on long-term suppressive ART, their highly polymorphic sequences and genetic structures, and the need for efficient lification and sequencing of the provirus and its integration site.
Publisher: American Society for Microbiology
Date: 15-01-2010
DOI: 10.1128/JVI.02204-09
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.TUBE.2020.102023
Abstract: To determine the association of human leukocyte antigen (HLA) alleles as correlates of risk for and protection against tuberculin skin test (TST) positivity and active TB disease amongst HIV-infected adults. Genomic DNA was extracted from 754 HIV-infected adults whole-blood. HLA-A, -B, -C and -DRB1 loci were genotyped by next generation sequencing methods. HLA alleles were analysed by the presence/absence of TST immune conversion and active TB disease and further stratified by exposure to a household TB contact, CD4 HLA-A*29:11 and - B*45:01/07 were associated with TST-positivity, while HLA-A*24:02, -A*29:02 and -B*15:16 with TST-negativity. In participants with a household TB contact, HLA-A*66:01, -A*68:02 and -B*49:01 were associated with TST-negativity. For TB disease, HLA-B*41:01, -C*06:02, -DRB1*04:01 and -DRB1*15:01 were associated with susceptibility, while HLA-B*07:02 and -DRB1*11:01 were protective, even for CD4 Several HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected in iduals. HLA associations may enable risk stratification of those with HIV infection. Protective alleles may assist in future TB vaccine development.
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
DOI: 10.1371/JOURNAL.PPAT.1009214
Abstract: The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected in iduals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed in iduals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p .001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.
Publisher: SAGE Publications
Date: 11-2008
DOI: 10.1177/135965350801300814
Abstract: We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting. We performed a diagnostic reassessment using a structured patient chart review in in iduals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these in iduals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score ≥2), uncertain (mean score ≥-1 and ≤1) and unlikely (mean score ≤-2). HLA typing was performed using sequence-based methods. From 131 reassessed in iduals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 in iduals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls ( P .001). HLA-B*5701 carriage rate was higher in in iduals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P .001). Only six (7%) HLA-B*5701-negative in iduals were classified as likely HSR after reassessment. HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative in iduals with minor symptoms among in iduals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify in iduals at high risk for ABC-HSR.
Publisher: Frontiers Media SA
Date: 13-10-2017
Publisher: Elsevier
Date: 2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
Publisher: American Society for Microbiology
Date: 15-04-2017
DOI: 10.1128/JVI.02133-16
Abstract: A deletion variant of the dengue virus (DENV) serotype 2 (DENV2) Tonga/74 strain lacking 30 nucleotides from its 3′ untranslated region (rDEN2Δ30) has previously been established for use in a controlled human DENV challenge model. To evaluate if this model is appropriate for the derivation of correlates of protection for DENV vaccines on the basis of cellular immunity, we wanted to compare the cellular immune response to this challenge strain to the response induced by natural infection. To achieve this, we predicted HLA class I- and class II-restricted peptides from rDEN2Δ30 and used them in a gamma interferon enzyme-linked immunosorbent spot assay to interrogate CD8 + and CD4 + T cell responses in healthy volunteers infected with rDEN2Δ30. At the level of CD8 responses, vigorous ex vivo responses were detected in approximately 80% of donors. These responses were similar in terms of the magnitude and the numbers of epitopes recognized to the responses previously observed in peripheral blood mononuclear cells from donors from regions where DENV is hyperendemic. The similarity extended to the immunodominance hierarchy of the DENV nonstructural proteins, with NS3, NS5, and NS1 being dominant in both donor cohorts. At the CD4 level, the responses to rDEN2Δ30 vaccination were less vigorous than those to natural DENV infection and were more focused on nonstructural proteins. The epitopes recognized following rDEN2Δ30 infection and natural infection were largely overlapping for both the CD8 (100%) and CD4 (85%) responses. Finally, rDEN2Δ30 induced stronger CD8 responses than other, more attenuated DENV isolates. IMPORTANCE The lack of a known correlate of protection and the failure of a neutralizing antibody to correlate with protection against dengue virus have highlighted the need for a human DENV challenge model to better evaluate the candidate live attenuated dengue vaccines. In this study, we sought to characterize the immune profiles of rDEN2Δ30-infected subjects and to compare the profiles with those for subjects from areas where DENV is hyperendemic. Our data demonstrate that T cell responses to rDENV2Δ30 are largely similar to those to natural infection in terms of specificity, highlighting that the response to this virus in humans is appropriate as a model for the T cell response to primary DENV2 infection.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-04-2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2002
DOI: 10.1097/00001432-200202000-00005
Abstract: Hyperlactatemia associated with use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) is not a single entity but a spectrum of abnormalities. The spectrum reflects varying degrees of derangement in systemic homeostasis in the face of primary drug effects on lactate load. Lactic acidosis, characterized by metabolic acidosis, blood lactate above 5 mmol/l, hepatic steatosis and high mortality, represents the extreme end of this spectrum where there is complete decompensation. Partially compensated states of lactate excess have now been described, ranging from less fulminant symptomatic hyperlactatemia with hepatic steatosis to chronic or intermittent low-grade hyperlactatemia without acidosis, steatosis or any symptoms. At a population level, average venous lactate concentrations do rise following treatment with NRTIs but stabilize long term in the majority of cases. The average increase in systemic lactate turnover that is required to maintain such compensated blood levels is not known and research into this may provide insights into the extent of incipient mitochondrial toxicity associated with chronic NRTI use. At a tissue-specific level, it is not known which tissues or organs (liver, fat, other) are the predominant contributors to an increase in systemic lactate load, nor whether the primary defect is one of increased production, decreased elimination or both.
Publisher: Frontiers Media SA
Date: 17-06-2021
DOI: 10.3389/FGENE.2021.642012
Abstract: Type B adverse drug reactions (ADRs) are iatrogenic immune-mediated syndromes with mechanistic etiologies that remain incompletely understood. Some of the most severe ADRs, including delayed drug hypersensitivity reactions, are T-cell mediated, restricted by specific human leukocyte antigen risk alleles and sometimes by public or oligoclonal T-cell receptors (TCRs), central to the immunopathogenesis of tissue-damaging response. However, the specific cellular signatures of effector, regulatory, and accessory immune populations that mediate disease, define reaction phenotype, and determine severity have not been defined. Recent development of single-cell platforms bringing together advances in genomics and immunology provides the tools to simultaneously examine the full transcriptome, TCRs, and surface protein markers of highly heterogeneous immune cell populations at the site of the pathological response at a single-cell level. However, the requirement for advanced bioinformatics expertise and computational hardware and software has often limited the ability of investigators with the understanding of diseases and biological models to exploit these new approaches. Here we describe the features and use of a state-of-the-art, fully integrated application for analysis and visualization of multiomic single-cell data called Visual Genomics Analysis Studio (VGAS). This unique user-friendly, Windows-based graphical user interface is specifically designed to enable investigators to interrogate their own data. While VGAS also includes tools for sequence alignment and identification of associations with host or organism genetic polymorphisms, in this review we focus on its application for analysis of single-cell TCR–RNA–Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-seq, enabling holistic cellular characterization by unbiased transcriptome and select surface proteome. Critically, VGAS does not require user-directed coding or access to high-performance computers, instead incorporating performance-optimized hidden code to provide application-based fast and intuitive tools for data analyses and production of high-resolution publication-ready graphics on standard specification laptops. Specifically, it allows analyses of comprehensive single-cell TCR sequencing (scTCR-seq) data, detailing (i) functional pairings of α–β heterodimer TCRs, (ii) one-click histograms to display entropy and gene rearrangements, and (iii) Circos and Sankey plots to visualize clonality and dominance. For unbiased single-cell RNA sequencing (scRNA-seq) analyses, users extract cell transcriptome signatures according to global structure via principal component analysis, t-distributed stochastic neighborhood embedding, or uniform manifold approximation and projection plots, with overlay of scTCR-seq enabling identification and selection of the immunodominant TCR-expressing populations. Further integration with similar sequence-based detection of surface protein markers using oligo-labeled antibodies (CITE-seq) provides comparative understanding of surface protein expression, with differential gene or protein analyses visualized using volcano plot or heatmap functions. These data can be compared to reference cell atlases or suitable controls to reveal discrete disease-specific subsets, from epithelial to tissue-resident memory T-cells, and activation status, from senescence through exhaustion, with more finite transcript expression displayed as violin and box plots. Importantly, guided tutorial videos are available, as are regular application updates based on the latest advances in bioinformatics and user feedback.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477970
Abstract: Supplementary Figure 5: The change in sTILs during NAC is not prognostic for outcome in TNBC patients with residual disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2006
DOI: 10.1097/01.QAI.0000224974.67962.CE
Abstract: Tissue mitochondrial DNA (mtDNA) levels have been proposed as a marker of nucleoside analouge reverse transcriptase inhibitor (NRTI) toxicity. However, clinical studies have yielded conflicting data regarding possible associations with mtDNA levels. This study examined mtDNA levels in matched s les of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from a large Australian cohort to examine treatment, clinical, and demographic associations with mtDNA depletion. mtDNA was quantified by real-time polymerase chain reaction. Results were compared across patient treatment and demographic details using linear mixed models. One hundred sixty-three PBMCs and 161 fat s les were available from 61 in iduals. Current NRTI exposure was the major determinant of mtDNA levels. Both ddI (didanosine) and d4T (stavudine) exposures were associated with mtDNA depletion in fat (P < or = 0.0001 vs. those not on NRTIs). DdI exposure (P = 0.003), but not d4T exposure (P = 0.5), was associated with mtDNA depletion in PBMCs. No association between patient demographics or time on current therapy and mtDNA was observed. Current NRTI exposure is the major determinant of tissue mtDNA, but the precise determinants are tissue specific. Both ddI and d4T exposure are associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs.
Publisher: The American Association of Immunologists
Date: 11-2017
Abstract: Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope–specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV− HCMV+ HLA-DR7+ cohort or with HLA-DR7–restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory–RA+ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell–transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+. The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477973
Abstract: Supplementary Figure 4: sTILs are not prognostic in ER+ or HER2+ disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477976
Abstract: Supplementary Figure 3: The prognostic value of sTILs is primarily confined to the post-NAC specimen in TNBC patients with residual disease.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
Publisher: Elsevier
Date: 2017
Publisher: Informa UK Limited
Date: 08-2004
Publisher: No publisher found
Date: 2014
Publisher: Cold Spring Harbor Laboratory
Date: 03-03-2021
DOI: 10.1101/2021.03.02.433156
Abstract: SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical s les, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene cycle threshold and days since symptom onset at s ling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median expression. We hypothesise that this is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern. The recently emerged and more transmissible SARS-CoV-2 lineage B.1.1.7 shows greater subgenomic RNA expression in clinical infections and enhanced expression of a noncanonical subgenomic RNA near ORF9b.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2009
Publisher: American Society for Microbiology
Date: 05-2014
DOI: 10.1128/JVI.00147-14
Abstract: The extent to which HIV-1 clade B strains exhibit population-specific adaptations to host HLA alleles remains incompletely known, in part due to incomplete characterization of HLA-associated HIV-1 polymorphisms (HLA-APs) in different global populations. Moreover, it remains unknown to what extent the same HLA alleles may drive significantly different escape pathways across populations. As the Japanese population exhibits distinctive HLA class I allele distributions, comparative analysis of HLA-APs between HIV-1 clade B-infected Japanese and non-Asian cohorts could shed light on these questions. However, HLA-APs remain incompletely mapped in Japan. In a cohort of 430 treatment-naive Japanese with chronic HIV-1 clade B infection, we identified 284 HLA-APs in Gag, Pol, and Nef using phylogenetically corrected methods. The number of HLA-associated substitutions in Pol, notably those restricted by HLA-B*52:01, was weakly inversely correlated with the plasma viral load (pVL), suggesting that the transmission and persistence of B*52:01-driven Pol mutations could modulate the pVL. Differential selection of HLA-APs between HLA subtype members, including those differing only with respect to substitutions outside the peptide-binding groove, was observed, meriting further investigation as to their mechanisms of selection. Notably, two-thirds of HLA-APs identified in Japan had not been reported in previous studies of predominantly Caucasian cohorts and were attributable to HLA alleles unique to, or enriched in, Japan. We also identified 71 cases where the same HLA allele drove significantly different escape pathways in Japan versus predominantly Caucasian cohorts. Our results underscore the distinct global evolution of HIV-1 clade B as a result of host population-specific cellular immune pressures. IMPORTANCE Cytotoxic T lymphocyte (CTL) escape mutations in HIV-1 are broadly predictable based on the HLA class I alleles expressed by the host. Because HLA allele distributions differ among worldwide populations, the pattern and ersity of HLA-associated escape mutations are likely to be somewhat distinct to each race and region. HLA-associated polymorphisms (HLA-APs) in HIV-1 have previously been identified at the population level in European, North American, Australian, and African cohorts however, large-scale analyses of HIV-1 clade B-specific HLA-APs in Asians are lacking. Differential intraclade HIV-1 adaptation to global populations can be investigated via comparative analyses of HLA-associated polymorphisms across ethnic groups, but such studies are rare. Here, we identify HLA-APs in a large Japanese HIV-1 clade B cohort using phylogenetically informed methods and observe that the majority of them had not been previously characterized in predominantly Caucasian populations. The results highlight HIV's unique adaptation to cellular immune pressures imposed by different global populations.
Publisher: Wiley
Date: 27-08-2007
Publisher: Wiley
Date: 07-2003
DOI: 10.1046/J.1468-1293.2003.00159.X
Abstract: To establish the prevalence, severity and factors associated with the HIV lipodystrophy syndrome. Cross-sectional study of lipodystrophy conducted in high HIV caseload primary care sites and HIV outpatient clinics. A subset of patients was examined using dual energy X-ray absorptiometry (DEXA) and single cut abdominal computerized tomography (CT) at the L4 vertebral level to quantify regional and total body fat. Factors associated with lipodystrophy, lipoatrophy and lipohypertrophy were assessed using multiple logistic regression based on assignment of cases and non-cases. One thousand, three hundred and forty-eight patients (95% male) were surveyed, 20% had AIDS, the mean CD4 lymphocyte count was 486 cells/microL, and 55% had <500 HIV-1 RNA copies/mL. Most participants (87%) had previously received or were currently receiving combination antiretroviral therapy, 73% with at least one protease inhibitor (PI) and 14% a non-PI-containing regimen. Lipodystrophy prevalence was 53% and of these, 55% reported both peripheral lipoatrophy and central lipohypertrophy, 31% experienced peripheral lipoatrophy only and 14% had central lipohypertrophy only. The prevalence of any body habitus change was 62% in PI-experienced patients, 33% in PI-naive patients and 21% in antiretroviral-naive patients. Lipodystrophy severity was less in antiretroviral-naive patients and most severe in PI-experienced patients. Increasing severity of lipodystrophy was both positively and significantly correlated with elevated liver enzymes, decreased testosterone levels, decreased skin-fold thickness, lower levels of total and peripheral fat (DEXA) and higher levels of visceral fat (CT). Lipodystrophy was also significantly associated with increasing age, symptomatic HIV disease, effective viral suppression, and increasing duration of therapy with both nucleoside reverse transcriptase inhibitors and PIs. The prevalence and severity of lipodystrophy reflects both length and type of treatment with antiretroviral therapy and is associated with decreased testosterone, increases in liver enzymes and greater suppression of HIV RNA. The reports of lipodystrophy in a small percentage of antiretroviral-naive patients suggests that factors other than antiretroviral therapy may be involved in the aetiology of this syndrome or that some conditions, such as wasting or age-associated obesity, may mimic lipoatrophy and lipohypertrophy, respectively.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-10-2007
Abstract: We studied CD8 T cell responses against HIV-1, cytomegalovirus, Epstein–Barr virus, and influenza in 128 subjects and demonstrate that polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. Interestingly, these protective CD8 T cells are equipped with low-avidity T cell receptors (TCRs) for the cognate virus epitope. Conversely, HLA-A-restricted epitopes are mostly associated with “only effector” IFN-γ-secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. These CD8 T cells are equipped with high-avidity TCR and express higher levels of the T cell exhaustion marker PD-1. Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses. These results provide the rationale for the observed protective role of HLA-B in HIV-1-infection and new insights into the relationship between TCR avidity, PD-1 expression, and the functional profile of CD8 T cells.
Publisher: Springer Science and Business Media LLC
Date: 05-07-0001
DOI: 10.1038/S42003-022-03565-9
Abstract: B.1.1.7 lineage SARS-CoV-2 is more transmissible, leads to greater clinical severity, and results in modest reductions in antibody neutralization. Subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool (periscope) to ARTIC Network Oxford Nanopore Technologies genomic sequencing data from 4400 SARS-CoV-2 positive clinical s les, we show that normalised sgRNA is significantly increased in B.1.1.7 (alpha) infections ( n = 879). This increase is seen over the previous dominant lineage in the UK, B.1.177 ( n = 943), which is independent of genomic reads, E cycle threshold and days since symptom onset at s ling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus in vitro. We hypothesise that increased ORF9b in B.1.1.7 is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles to evaluate emerging potential variants of concern.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 10-11-2021
DOI: 10.1101/2021.11.09.21266140
Abstract: The COVID-19 pandemic has greatly impacted school operations. To better understand the role of schools in COVID-19 transmission, we evaluated infections at two independent schools in Nashville, TN during the 2020-2021 school year. The cumulative incidence of COVID-19 within each school, age group, and exposure setting were estimated and compared to local incidence. Primary attack rates were estimated among students quarantined for in-school close contact. Among 1401 students who attended school during the study period, 98 cases of COVID-19 were reported, corresponding to cumulative incidence of 7.0% (95% confidence interval (CI): 5.7-8.5). Most cases were linked to household (58%) or community (31%) transmission, with few linked to in-school transmission (11%). Overall, 619 students were quarantined, corresponding to person-days of missed school, among whom only 5 tested positive for SARS-CoV-2 during quarantine (primary attack rate: 0.8%, 95% CI: 0.3, 1.9). Weekly case rates at school were not correlated with community transmission. These results suggest that transmission of COVID-19 in schools is minimal when strict mitigation measures are used, even during periods of extensive community transmission. Strict quarantine of contacts may lead to unnecessary missed school days with minimal benefit to in-school transmission.
Publisher: Wiley
Date: 05-2005
DOI: 10.1111/J.1468-1293.2005.00280.X
Abstract: To assess the impact of highly active antiretroviral therapy (HAART) on rates of change of antiretroviral treatment among patients co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in the Australian HIV Observational Database (AHOD). Analysis was based on 805 of the 2218 patients recruited to the AHOD by March 2003, who had commenced HAART after 1 January 1997, who had recorded test results for HBV surface antigen and anti-HCV antibody, and who had follow-up of more than 3 months. The effect of hepatitis co-infection on the rate of antiretroviral treatment change after commencing HAART was assessed using a random-effect Poisson regression model. Among those included in the analyses, the prevalences of HBV and HCV were 4.8% and 12.8%, respectively. The overall rate of combination antiretroviral treatment change was 0.74 combinations per year. Factors independently associated with an increased rate of change of combination antiretroviral treatment were: prior AIDS-defining illness prior exposure to double combination antiretroviral therapy and antiretroviral treatment class. Co-infection with HBV and/or HCV was not found to be significantly associated with the rate of combination antiretroviral treatment change. While both HBV and HCV co-infections are relatively common in the AHOD, they do not appear to be serious impediments to the treatment of HIV-infected patients.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 21-06-2017
DOI: 10.1038/NATURE22815
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Publisher: Elsevier BV
Date: 2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477988
Abstract: Supplementary Figure 15: Differential analysis to identify candidate genes for blood-based detection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2021
Publisher: American Society for Microbiology
Date: 15-01-2018
DOI: 10.1128/JVI.01128-17
Abstract: HIV circumvents HLA class I-restricted CD8 + T-cell responses through selection of escape mutations that leave characteristic mutational “footprints,” also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive in iduals from Mexico and 1,641 in iduals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of .2, 358 HAPs (201 in Gag, 157 in PR-RT) were identified in Mexico, while 905 (534 in Gag and 371 in PR-RT) were identified in Canada/United States. HAPs identified in Mexico included both canonical HLA-associated escape pathways and novel associations, in particular with HLA alleles enriched in Amerindian and mestizo populations. Remarkably, HLA footprints on HIV in Mexico were not only fewer but also, on average, significantly weaker than those in Canada/United States, although some exceptions were noted. Moreover, exploratory analyses suggested that the weaker HLA footprint on HIV in Mexico may be due, at least in part, to weaker and/or less reproducible HLA-mediated immune pressures on HIV in this population. The implications of these differences for natural and vaccine-induced anti-HIV immunity merit further investigation. IMPORTANCE HLA footprints on HIV identify viral regions under intense and consistent pressure by HLA-restricted immune responses and the common mutational pathways that HIV uses to evade them. In particular, HLA footprints can identify novel immunogenic regions and/or epitopes targeted by understudied HLA alleles moreover, comparative analyses across immunogenetically distinct populations can illuminate the extent to which HIV immunogenic regions and escape pathways are shared versus population-specific pathways, information which can in turn inform the design of universal or geographically tailored HIV vaccines. We compared HLA-associated footprints on HIV in two immunogenetically distinct North American populations, those of Mexico and Canada/United States. We identify both shared and population-specific pathways of HIV adaptation but also make the surprising observation that HLA footprints on HIV in Mexico overall are fewer and weaker than those in Canada/United States, raising the possibility that HLA-restricted antiviral immune responses in Mexico are weaker, and/or escape pathways somewhat less consistent, than those in other populations.
Publisher: Public Library of Science (PLoS)
Date: 04-07-2007
Publisher: Public Library of Science (PLoS)
Date: 09-08-2019
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477988.V1
Abstract: Supplementary Figure 15: Differential analysis to identify candidate genes for blood-based detection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-12-2008
DOI: 10.1002/HEP.22773
Abstract: The efficacy of specifically targeted anti-viral therapy for hepatitis C virus (HCV) (STAT-C), including HCV protease and polymerase inhibitors, is limited by the presence of drug-specific viral resistance mutations within the targeted proteins. Genetic ersity within these viral proteins also evolves under selective pressures provided by host human leukocyte antigen (HLA)-restricted immune responses, which may therefore influence STAT-C treatment response. Here, the prevalence of drug resistance mutations relevant to 27 developmental STAT-C drugs, and the potential for drug and immune selective pressures to intersect at sites along the HCV genome, is explored. HCV nonstructural (NS) 3 protease or NS5B polymerase sequences and HLA assignment were obtained from study populations from Australia, Switzerland, and the United Kingdom. Four hundred five treatment-naïve in iduals with chronic HCV infection were considered (259 genotype 1, 146 genotype 3), of which 38.5% were coinfected with human immunodeficiency virus (HIV). We identified preexisting STAT-C drug resistance mutations in sequences from this large cohort. The frequency of the variations varied according to in idual STAT-C drug and HCV genotype/subtype. Of in iduals infected with subtype 1a, 21.5% exhibited genetic variation at a known drug resistance site. Furthermore, we identified areas in HCV protease and polymerase that are under both potential HLA-driven pressure and therapy selection and identified six HLA-associated polymorphisms (P <or= 0.05) at known drug resistance sites. Drug and host immune responses are likely to provide powerful selection forces that shape HCV genetic ersity and replication dynamics. Consideration of HCV viral adaptation in terms of drug resistance as well as host "immune resistance" in the STAT-C treatment era could provide important information toward an optimized and in idualized therapy for chronic hepatitis C.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-07-2022
DOI: 10.1161/CIRCRESAHA.122.321116
Abstract: CD (cluster of differentiation) 4 + T-cell responses to APOB (apolipoprotein B) are well characterized in atherosclerotic mice and detectable in humans. CD4 + T cells recognize antigenic peptides displayed on highly polymorphic HLA (human leukocyte antigen)-II. Immunogenicity of in idual APOB peptides is largely unknown in humans. Only 1 HLA-II-restricted epitope was validated using the DRB1*07:01-APOB 3036 –3050 tetramer. We hypothesized that human APOB may contain discrete immunodominant CD4 + T-cell epitopes that trigger atherosclerosis-related autoimmune responses in donors with erse HLA alleles. We selected 20 APOB-derived peptides (APOB 20 ) from an in silico screen and experimentally validated binding to the most commonly occurring human HLA-II alleles. We optimized a restimulation-based workflow to evaluate antigenicity of multiple candidate peptides in HLA-typed donors. This included activation-induced marker assay, intracellular cytokine staining, IFNγ (interferon gamma) enzyme–linked immunospot and cytometric bead array. High-throughput sequencing revealed TCR (T-cell receptor) clonalities of APOB-reactive CD4 + T cells. Using stringent positive, negative, and crossover stimulation controls, we confirmed specificity of expansion-based protocols to detect CD4 + T cytokine responses to the APOB 20 pool. Ex vivo assessment of AIM + CD4 + T cells revealed a statistically significant autoimmune response to APOB 20 but not to a ubiquitously expressed negative control protein, actin. Resolution of CD4 + T responses to the level of in idual peptides using IFNγ enzyme–linked immunospot led to the discovery of 6 immunodominant epitopes (APOB 6 ) that triggered robust CD4 + T activation in most donors. APOB 6 -specific responding CD4 + T cells were enriched in unique expanded TCR clonotypes and preferentially expressed memory markers. Cytometric bead array analysis detected APOB 6 -induced secretion of both proinflammatory and regulatory cytokines. In clinical s les from patients with angiographically verified coronary artery disease, APOB 6 stimulation induced higher activation and memory phenotypes and augmented secretion of proinflammatory cytokines TNF (tumor necrosis factor) and IFNγ, compared with patients with low coronary artery disease. Using 3 cohorts, each with ≈20 donors, we discovered and validated 6 immunodominant, HLA-II–restricted APOB epitopes. The immune response to these APOB epitopes correlated with coronary artery disease severity.
Publisher: Public Library of Science (PLoS)
Date: 13-09-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1097/00002030-200501030-00014
Abstract: Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2016
DOI: 10.1038/NM.4100
Publisher: Elsevier BV
Date: 06-1990
DOI: 10.1016/0140-6736(90)91418-A
Abstract: A questionnaire was used to assess general practitioners' knowledge of handicaps and service use among disabled patients in a group practice. The disabled patients were identified by a postal screening questionnaire. Sixty-eight were subsequently interviewed to assess the severity of restrictions on their activities and to collect information about informal support and use of community or hospital services. The areas of life in which the disabled were most affected by their medical conditions were sleep and rest, household management, emotion and mood. Relatives assisted the disabled considerably with all daily activities but more help was requested. Most disabled patients had consulted their general practitioner or attended casualty and outpatient clinics, but only a minority had used other community services. Prescription of drugs was considered the most important service the doctor provided. A second questionnaire, which the general practitioners completed with the help of their records, revealed that they knew of only 50 per cent of the difficulties with daily living reported by the disabled and even less of the aids, appliances and services used. A better awareness of these facilities among general practitioners might lead to a more effective distribution of resources among their patients.
Publisher: Informa UK Limited
Date: 03-2006
DOI: 10.1310/4733-ACQF-F3P4-2QAC
Abstract: ESPRIT, is a phase III, open-label, randomized, international clinical trial evaluating the effects of subcutaneous recombinant interleukin-2 (rIL-2) plus antiretroviral therapy (ART) versus ART alone on HIV-disease progression and death in HIV-1-infected in iduals with CD4+ T-cells > or =300 cells/microL. To describe the baseline characteristics of participants randomized to ESPRIT overall and by geographic location. Baseline characteristics of randomized participants were summarized by region. 4,150 patients were enrolled in ESPRIT from 254 sites in 25 countries. 41%, 27%, 16%, 11%, and 5% were enrolled in Europe, North America, South America, Asia, and Australia, respectively. The median age was 40 years, 81% were men, and 76%, 11%, and 9% were Caucasian, Asian, and African American or African, respectively. 44% of women enrolled (n = 769) were enrolled in Thailand and Argentina. Overall, 55% and 38% of the cohort acquired HIV through male homosexual and heterosexual contact, respectively. 25% had a prior history of AIDS-defining illness Pneumocystis jirovecii pneumonia, M. tuberculosis, and esophageal candida were most commonly reported. Median nadir and baseline CD4+ T-cell counts were 199 and 458 cells/muL, respectively. 6% and 13% were hepatitis B or C virus coinfected, respectively. Median duration of antiretroviral therapy (ART) was 4.2 years the longest median duration was in Australia (5.2 years) and the shortest was in Asia (2.3 years). 17%, 13%, and 69% of participants began ART before 1995, between 1996 and 1997, and from 1998 onward, respectively. 86% used ART from two or more ART classes, with 49% using a protease inhibitor-based regimen and 46% using a nonnucleoside reverse transcriptase inhibitor-based regimen. 78% had plasma HIV RNA below detection (<500 cp/mL). ESPRIT has enrolled a erse population of HIV-infected in iduals including large populations of women and patients of African-American/African and Asian ethnicity often underrepresented in HIV research. As a consequence, the results of the study may have wide global applicability.
Publisher: Elsevier BV
Date: 06-2008
Publisher: Wiley
Date: 09-2017
DOI: 10.1002/PHAR.1983
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-01-2007
Publisher: American Society for Microbiology
Date: 02-2011
DOI: 10.1128/JVI.01966-10
Abstract: The high ersity of HLA binding preferences has been driven by the sequence ersity of short segments of relevant pathogenic proteins presented by HLA molecules to the immune system. To identify possible commonalities in HLA binding preferences, we quantify these using a novel measure termed “targeting efficiency,” which captures the correlation between HLA-peptide binding affinities and the conservation of the targeted proteomic regions. Analysis of targeting efficiencies for 95 HLA class I alleles over thousands of human proteins and 52 human viruses indicates that HLA molecules preferentially target conserved regions in these proteomes, although the arboviral Flaviviridae are a notable exception where nonconserved regions are preferentially targeted by most alleles. HLA-A alleles and several HLA-B alleles that have maintained close sequence identity with chimpanzee homologues target conserved human proteins and DNA viruses such as Herpesviridae and Adenoviridae most efficiently, while all HLA-B alleles studied efficiently target RNA viruses. These patterns of host and pathogen specialization are both consistent with coevolutionary selection and functionally relevant in specific cases for ex le, preferential HLA targeting of conserved proteomic regions is associated with improved outcomes in HIV infection and with protection against dengue hemorrhagic fever. Efficiency analysis provides a novel perspective on the coevolutionary relationship between HLA class I molecular ersity, self-derived peptides that shape T-cell immunity through ontogeny, and the broad range of viruses that subsequently engage with the adaptive immune response.
Publisher: Public Library of Science (PLoS)
Date: 17-05-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477994.V1
Abstract: Supplementary Figure 13: Purity-of-sort analysis.
Publisher: American Thoracic Society
Date: 2016
Publisher: Oxford University Press (OUP)
Date: 02-2006
DOI: 10.1086/499369
Publisher: Elsevier BV
Date: 12-2018
Publisher: Informa UK Limited
Date: 08-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2006
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477991
Abstract: Supplementary Figure 14: Differentially expressed genes by cluster in whole blood single cell RNA sequencing.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477994
Abstract: Supplementary Figure 13: Purity-of-sort analysis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529814.V1
Abstract: AbstractPurpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME). Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1 sup HI /sup ) CD8 sup + /sup peripheral T cells and examination of a cytolytic gene signature in whole blood. Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden. Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence. /
Publisher: Future Medicine Ltd
Date: 08-2012
DOI: 10.2217/PGS.12.108
Abstract: Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens–Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost–effectiveness of drug design and development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2016
DOI: 10.1161/CIRCRESAHA.115.308111
Abstract: Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity. To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges. We imposed repeated hypertensive challenges using either N ω -nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T EM ) accumulated in the kidney and bone marrow. In the L-NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-γ and interleukin-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T EM cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow–residing T EM cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T EM cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice. Our findings illustrate a previously undefined role of CD70 and long-lived T EM cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific T EM cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477997
Abstract: Supplementary Figure 12: TCRβ repertoires in the post-NAC residual disease or tumor scar are most like PD-1HI CD8+ peripheral repertoires.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Public Library of Science (PLoS)
Date: 10-12-2019
Publisher: Wiley
Date: 09-1995
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Publisher: Springer Science and Business Media LLC
Date: 03-2005
DOI: 10.1038/NI0305-232
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/ATVBAHA.120.315786
Abstract: Persons with HIV have double the risk of developing cardiovascular disease compared with the general population. A persistent and heightened immune response to cytomegalovirus coinfection may be one contributing factor, but the relationship between cytomegalovirus replication, virus-specific immune cells, and plaque burden is unclear. We assessed the relationship between CD4 + T-cell subsets and carotid plaque burden in a cohort of 70 HIV-positive participants with sustained viral suppression on a single antiretroviral regimen and without known cardiovascular disease. We evaluated relationships between immune parameters, carotid plaque burden, and brachial artery flow-mediated vasodilation using multivariable linear and logistic regression models. We found that participants with carotid plaque had increased circulating CX3CR1 + ~GPR56 + ~CD57 + (ie, C~G~C) + CD4 + T cells ( P =0.03), which is a marker combination associated with antiviral and cytotoxic responses. In addition, a median of 14.4% (IQR, 4.7%–32.7%) of the C~G~C + CD4 + T-cells expressed antigen receptors that recognized a single cytomegalovirus glycoprotein-B epitope. Using immunofluorescence staining, we found that CX3CR1 + CD4 + T cells were present in coronary plaque from deceased HIV-positive persons. C~G~C + CD4 + T cells were also present in cells isolated from the aorta of HIV-negative donors. HIV-positive persons with carotid atheroma have a higher proportion of circulating CD4 + T-cells expressing the C~G~C surface marker combination associated with antiviral and cytotoxic responses. These cells can be cytomegalovirus-specific and are also present in the aorta.
Publisher: Elsevier BV
Date: 07-2008
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.MOLIMM.2004.07.041
Abstract: The Killer Ig-like receptors (KIRs) on NK cells regulate NK activity via the recognition of specific HLA class I products on the surface of target cells. To investigate the level at which these genetically polymorphic receptors and ligands influence HIV-1 disease progression, we examined the effect of KIR and HLA genotype on HIV outcome. We observed a significant association between particular combinations of KIR epitopes expressed by HLA-B/-C haplotypes and propose that the repertoire of KIR epitopes expressed by HLA-B and HLA-C alleles within the context of particular haplotypes may be an important component of the NK mediated immune response to HIV and/or other infectious pathogens.
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: Elsevier BV
Date: 2018
Publisher: Public Library of Science (PLoS)
Date: 12-02-2015
Publisher: Frontiers Media SA
Date: 19-03-2019
Publisher: Elsevier BV
Date: 12-1990
DOI: 10.1016/0198-8859(90)90042-N
Abstract: Several alleles at multiple HLA loci have been found to be associated with infection with human immunodeficiency virus (HIV): HLA A1 B8, B35 Cw7, Cw4 DR1, DR3 and DQ1, are associated with particular disease manifestations and/or disease progression. Furthermore, in a pilot study we have shown an increase in the frequency of C4 null alleles and suggested that all the reported HLA alleles could reflect association with a limited number of ancestral haplotypes (AHs). On this occasion, we studied 122 Caucasoid patients classified according to Centers for Disease Control (CDC) criteria. The control group consisted of 67 seronegative homosexual or bisexual males at risk of developing HIV infection. C4 null alleles were unequivocally present in 58% of patients in CDC IV compared with 33% of the seronegative subjects (chi 2 = 5.65, p less than 0.05). Furthermore, C4 null alleles could be excluded in only 8% and 16% of CDC III and IV, respectively, but in 30% of the seronegative subjects. An increased frequency of three AHs largely accounted for the increases in C4 null and HLA alleles. To examine the role of specific AHs we undertook a longitudinal analysis of a subgroup of 26 patients who seroconverted under observation. Seventeen of these patients were followed for 32 to 63 months. All seven patients with the 8.1 AH (A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) developed low CD4 lymphocyte counts (less than 450 x 10(6)/l) compared with only 2 of 10 patients without this haplotype (p less than 0.002). All three deaths occurred in patients with the 8.1 AH. The acquired immunodeficiency syndrome developed in three further cases with either 8.1- or B35-bearing (35.x) haplotypes. Sequential CD4/8 ratios showed an early and progressive decline in in iduals with 8.1 or 35.x. Since the 8.1 and 35.x AHs contain deletions of the central major histocompatibility complex (MHC) genes, we suggest that the genes affecting HIV infection and progression are within the central MHC region.
Publisher: American Society for Microbiology
Date: 25-03-2021
DOI: 10.1128/JVI.02380-20
Abstract: Human T cells recognize portions of viral proteins bound to host molecules (human leukocyte antigens) on the surface of infected cells. T cells recognize these foreign proteins through their T cell receptors (TCRs), which are formed by the assortment of several available V, D, and J genes to create millions of combinations of unique TCRs.
Publisher: Frontiers Media SA
Date: 26-04-2018
Publisher: Public Library of Science (PLoS)
Date: 31-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477982.V1
Abstract: Supplementary Figure 17: An 8-gene activated T cell signature derived from whole blood at surgery is associated with residual disease burden and recurrence.
Publisher: MDPI AG
Date: 12-11-2020
DOI: 10.3390/V12111300
Abstract: Yellow fever virus (YFV) is a mosquito-borne member of the genus flavivirus, including other important human-pathogenic viruses, such as dengue, Japanese encephalitis, and Zika. Herein, we report identifying 129 YFV Class II epitopes in donors vaccinated with the live attenuated YFV vaccine (YFV-17D). A total of 1156 peptides predicted to bind 17 different common HLA-DRB1 allelic variants were tested using IFNγ ELISPOT assays in vitro re-stimulated peripheral blood mononuclear cells from twenty-six vaccinees. Overall, we detected responses against 215 YFV epitopes. We found that the capsid and envelope proteins, as well as the non-structural (NS) proteins NS3 and NS5, were the most targeted proteins by CD4+ T cells from YF-VAX vaccinated donors. In addition, we designed and validated by flow cytometry a CD4+ mega pool (MP) composed of structural and non-structural epitopes in an independent cohort of vaccinated donors. Overall, this study provides a comprehensive prediction and validation of YFV epitopes in a cohort of YF-17D vaccinated in iduals. With the design of a CD4 epitope MP, we further provide a useful tool to detect ex vivo responses of YFV-specific CD4 T cells in small s le volumes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477976.V1
Abstract: Supplementary Figure 3: The prognostic value of sTILs is primarily confined to the post-NAC specimen in TNBC patients with residual disease.
Publisher: Public Library of Science (PLoS)
Date: 12-01-2017
Publisher: Bangladesh Journals Online (JOL)
Date: 04-01-2021
Abstract: Abstract not available Bangladesh J Medicine January 2021 32(1) : 58-61
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-05-2017
DOI: 10.1126/SCITRANSLMED.AAI8708
Abstract: Numerous associations were discovered between human leukocyte antigen (HLA) variation and a comprehensive set of phenotypes derived from electronic health records.
Publisher: American Society for Microbiology
Date: 21-07-2022
DOI: 10.1128/IAI.00004-22
Abstract: To evaluate potential effects of gastric inflammation on Helicobacter pylori ersification and evolution within the stomach, we experimentally infected Mongolian gerbils with an H. pylori strain in which Cag type IV secretion system (T4SS) activity is controlled by a TetR/ tetO system. Gerbils infected with H. pylori under conditions in which Cag T4SS activity was derepressed had significantly higher levels of gastric inflammation than gerbils infected under conditions with repressed Cag T4SS activity.
Publisher: Cold Spring Harbor Laboratory
Date: 13-06-2018
DOI: 10.1101/346650
Abstract: Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified a physical interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in an SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.
Publisher: Oxford University Press (OUP)
Date: 20-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-01-2013
Publisher: The American Association of Immunologists
Date: 03-2016
Abstract: The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence- ergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1–reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV–VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2001
DOI: 10.1097/00002030-200109280-00010
Abstract: Lipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution. Eighty-one HIV protease inhibitor recipients (78 male mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48. There was a greater decline in total body fat in the switch group than in the continue group (-1.6 and -0.4 kg, respectively at week 24 P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter. In predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.
Publisher: Elsevier
Date: 2008
Publisher: Public Library of Science (PLoS)
Date: 24-12-2009
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S1386-6532(02)00134-8
Abstract: A number of international research groups have developed DNA quantitation assays in order to investigate the role of mitochondrial DNA depletion in anti-retroviral therapy-induced toxicities. A collaborative study was undertaken to evaluate intra-assay precision and between laboratory concordance of measurements of mitochondrial DNA quantity, as a component of a comprehensive quality assurance project. Four laboratories were asked to measure and report mitochondrial DNA and nuclear DNA genome copy number, as well as mitochondrial DNA copy number/cell, for 17 coded aliquots of DNA derived from serial dilutions of pooled DNA from a lymphoblastoid cell line. S les included masked replicates and five standards. All s les had similar mitochondrial DNA/nuclear DNA ratios. Precision within laboratories was assessed by determining the coefficient of variation of replicates. Concordance between laboratories was assessed by determining the average coefficient of variation of the mean replicate values for each s le. The effect of standardising the assay for these three measurements was also assessed for laboratories A, B and C. Measurements of mitochondrial DNA and nuclear DNA content for replicate s les varied by an average of less than 6% (based on log(10) values, 72% non-logged values), and measurements of mitochondrial DNA/cell for replicates varied by less than 12% (based on log(10) values, 32% non-logged values), with no improvement of precision after standardisation. Standardisation did significantly improve the concordance of results for measurements of mitochondrial DNA content and mitochondrial DNA/cell. Non-standardised measurements of mitochondrial DNA content for the same s le set varied by 19% between laboratories (based on log(10) values, 96% non-logged values), and after standardisation results varied by less than 3% (based on log(10) values, 54% non-logged values). There was no significant improvement for concordance of measures of nuclear DNA content after standardisation, with results varying by 4.56% between laboratories (based on log(10) values, 45% non-logged values) before standardisation, and by 2.49% (based on log(10) values, 50% non-logged values) after standardisation. Derived values of mitochondrial DNA/cell varied between laboratories by an average of 91% (non-logged, 56% log(10) values) before and by 56% (non-logged, 13% log(10) values) after standardisation. All assays demonstrated good precision. The use of common standards is an important step in improving the comparability of data between laboratories.
Publisher: Oxford University Press (OUP)
Date: 28-09-2020
Abstract: Chronic norovirus infection in immunocompromised patients can be severe, and presently there is no effective treatment. Adoptive transfer of virus-specific T cells has proven to be safe and effective for the treatment of many viral infections, and this could represent a novel treatment approach for chronic norovirus infection. Hence, we sought to generate human norovirus-specific T cells (NSTs) that can recognize different viral sequences. Norovirus-specific T cells were generated from peripheral blood of healthy donors by stimulation with overlapping peptide libraries spanning the entire coding sequence of the norovirus genome. We successfully generated T cells targeting multiple norovirus antigens with a mean 4.2 ± 0.5-fold expansion after 10 days. Norovirus-specific T cells comprised both CD4+ and CD8+ T cells that expressed markers for central memory and effector memory phenotype with minimal expression of coinhibitory molecules, and they were polyfunctional based on cytokine production. We identified novel CD4- and CD8-restricted immunodominant epitopes within NS6 and VP1 antigens. Furthermore, NSTs showed a high degree of cross-reactivity to multiple variant epitopes from clinical isolates. Our findings identify immunodominant human norovirus T-cell epitopes and demonstrate that it is feasible to generate potent NSTs from third-party donors for use in antiviral immunotherapy.
Publisher: Massachusetts Medical Society
Date: 07-02-2008
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/S0163-4453(95)80010-7
Abstract: Cytomegalovirus (CMV) is an increasingly important opportunistic pathogen in patients with HIV infection and advanced immune deficiency. Neurological complications due to CMV cause significant morbidity but may be treatable with specific anti-viral therapy: cerebral mass lesions are not a generally recognised manifestation. We report two patients with CMV encephalitis presenting as a cerebral mass lesion, with simultaneous occurrence of a pleuro-pulmonary mass also caused by CMV in one case, and with concurrent polyradiculomyelopathy in the other. The spectrum of previously reported clinical and radiological features of CNS involvement in AIDS is discussed. CMV should be considered in the differential diagnosis of cerebral mass lesions in patients with HIV infection and severe immune deficiency so that anti-viral therapy can be rapidly deployed.
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2021
Abstract: We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed “subgenomic RNAs.” sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5′ UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5′ end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2 +/− cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 s les worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2001
Publisher: American Society of Hematology
Date: 07-07-2011
DOI: 10.1182/BLOOD-2010-06-291963
Abstract: Obstacles to developing an HIV-1 vaccine include extensive viral ersity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1–specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 ersity, making it difficult to disentangle the contribution of CTL selection without using complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many persons contemporaneously. The genetic ergence now evident in these subjects should uniquely reveal how much viral ersity at the population level is solely attributable to host factors. We found significant correlations between pair-wise ergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, reverse transcriptase, integrase, and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these 4 proteins, 24%-56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major effect on inter-host HIV-1 viral ersity and probably represents a key element of viral control.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2000
DOI: 10.1097/00002030-200007070-00002
Abstract: Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy. To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients. Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study. The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses. Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year P < 0.0001), white race (relative risk = 3.9 P = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month P = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month P < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time. NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose in iduals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
Publisher: Annual Reviews
Date: 14-01-2015
DOI: 10.1146/ANNUREV-MED-050913-022745
Abstract: The immunological mechanisms driving delayed hypersensitivity reactions (HSRs) to drugs mediated by drug-reactive T lymphocytes are exemplified by several key ex les and their human leukocyte antigen (HLA) associations: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02, allo-purinol and HLA-B*58:01, and both amoxicillin-clavulanate and nevirapine with multiple class I and II alleles. For HLA-restricted drug HSRs, specific class I and/or II HLA alleles are necessary but not sufficient for tissue specificity and the clinical syndrome. Several models have been proposed to explain the immunopathogenesis of severe T cell–mediated drug HSRs, and our increased understanding of the risk factors and mechanisms involved in the development of these reactions will further the development of sensitive and specific strategies for preclinical screening that will lead to safer and more cost-effective drug design.
Publisher: MDPI AG
Date: 22-04-2016
DOI: 10.3390/V8040118
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2003
DOI: 10.1097/00126334-200305010-00005
Abstract: HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. The investigation was a prospective, randomized, controlled, open-label study. The subjects included 37 HIV-1-infected in iduals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor. Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 in iduals had adverse reactions to abacavir therapy. A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor.
Publisher: Springer Science and Business Media LLC
Date: 03-2009
DOI: 10.1007/BF03256308
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2008
Publisher: The American Association of Immunologists
Date: 07-2019
Abstract: Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau–derived peptides between PD patients, age-matched healthy controls, and young healthy controls (& y old who are less likely to have high levels of tau aggregates). All groups exhibited CD4+ T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.
Publisher: American Society for Microbiology
Date: 14-09-2022
DOI: 10.1128/JVI.01191-22
Abstract: Despite decades of research, an effective HIV-1 vaccine remains elusive. Vaccine strategies leading to the generation of broadly neutralizing antibodies are likely needed to provide the best opportunity of generating a protective immune response against HIV-1.
Publisher: Rockefeller University Press
Date: 21-03-2005
DOI: 10.1084/JEM.20041455
Abstract: Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two ex les of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2017
Publisher: American Society for Microbiology
Date: 11-2005
DOI: 10.1128/JVI.79.21.13239-13249.2005
Abstract: The sequence ersity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8 + T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8 + T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8 + T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both in idual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2009
DOI: 10.1038/NATURE07746
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478006.V1
Abstract: Supplementary Figure 1: Representative images of high and low sTILs.
Publisher: Frontiers Media SA
Date: 24-01-2022
DOI: 10.3389/FCIMB.2021.781968
Abstract: The upper respiratory tract (URT) is the portal of entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and SARS-CoV-2 likely interacts with the URT microbiome. However, understanding of the associations between the URT microbiome and the severity of coronavirus disease 2019 (COVID-19) is still limited. Our primary objective was to identify URT microbiome signature/s that consistently changed over a spectrum of COVID-19 severity. Using data from 103 adult participants from two cities in the United States, we compared the bacterial load and the URT microbiome between five groups: 20 asymptomatic SARS-CoV-2-negative participants, 27 participants with mild COVID-19, 28 participants with moderate COVID-19, 15 hospitalized patients with severe COVID-19, and 13 hospitalized patients in the ICU with very severe COVID-19. URT bacterial load, bacterial richness, and within-group microbiome composition dissimilarity consistently increased as COVID-19 severity increased, while the relative abundance of an licon sequence variant (ASV), Corynebacterium _unclassified.ASV0002, consistently decreased as COVID-19 severity increased. We observed that the URT microbiome composition significantly changed as COVID-19 severity increased. The URT microbiome could potentially predict which patients may be more likely to progress to severe disease or be modified to decrease severity. However, further research in additional longitudinal cohorts is needed to better understand how the microbiome affects COVID-19 severity.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478012.V1
Abstract: Dataset 2: Metadata and clonotype data for TCRβ sequencing (Archer) in 4 patients (peripheral CD8+ PD-1HI and CD8+ PD-1NEG T cells and post-NAC tumor), before (n=3) and after (n=4) NAC.
Publisher: American Society for Microbiology
Date: 15-08-2007
DOI: 10.1128/JVI.02823-07
Publisher: Wiley
Date: 19-04-2011
DOI: 10.1111/J.1399-0039.2011.01649.X
Abstract: HLA-B57 and HLA-B58 are major histocompatibility class (MHC)-I allotypes that are potentially predictive of important clinical immune phenotypes. HLA-B*5701 is strongly associated with hypersensitivity to the HIV drug abacavir, liver toxicity from the antibiotic flucloxacillin and is a marker for slow progression of HIV AIDS. HLA-B*5801 is associated with hypersensitivity to allopurinol used to treat hyperuricaemia and recurrent gout. Here we describe a monoclonal antibody (mAb) specific for HLA-B57 and HLA-B58 that provides an inexpensive and sensitive screen for these MHC-I allotypes. The usefulness of HLA-B57 screening for prediction of abacavir hypersensitivity was shown in three independent laboratories, including confirmation of the mAb sensitivity and specificity in a cohort of patients enrolled in the PREDICT-1 trial. Our data show that patients who test negative by mAb screening comprise 90%-95% of all in iduals in most human populations and require no further human leukocyte antigen (HLA) typing. Patients who test positive by mAb screening should proceed to high-resolution typing to ascertain the presence of HLA-B*5701 or HLA-B*5801. Hence, mAb screening provides a low-cost alternative to high-resolution typing of all patients and lends itself to point-of-care diagnostics and rapid ascertainment of low-risk patients who can begin immediate therapy with abacavir, flucloxacillin or allopurinol.
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/SH11181
Abstract: Background: In Australia, temporary visa holders are ineligible for Medicare and subsidised antiretroviral drugs. Additionally, HIV testing is not mandatory for visas unless applicants seek work in the health sector. We sought to understand the impact of HIV and issues of access and adherence to antiretroviral therapy (ART) in people holding temporary visas and permanent residents. Methods: Data were gathered from interviews with 22 participants. Information concerning medication adherence, side effects, CD4 T-cell count, viral load and rate of response to generic drugs were collected. Results: The mean age was 33.4 years (±s.d. = 6.0), 21 out of 22 were from HIV-prevalent areas in East Africa and Asia, 14 out of 22 were on temporary visas, 12 were ineligible for Medicare, 14 out of 22 were diagnosed during health screening, 19 out of 22 risk exposures were in country of origin, 8 out of 17 were taking generic ART at an average cost of $180 per month, adherence was excellent and self-reported side-effects were relatively infrequent. Participants applying for visa continuations and permanent residency were fearful, believing their HIV serostatus would prejudice their applications. Patients cited belief in ART efficacy, were motivated to maintain therapy and were anxious about lack of access to treatment in their countries of origin. Conclusion: Adherence to antiretroviral drugs in Medicare-ineligible HIV-infected in iduals is excellent despite limited access to treatment. The threat of visa non-renewal and the likely failure of applications for permanent residency result in considerable anxiety and confidentiality concerns.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2012
Abstract: Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8 + T cells that required HLA-B*57:01 molecules for their function however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477973.V1
Abstract: Supplementary Figure 4: sTILs are not prognostic in ER+ or HER2+ disease.
Publisher: American Society for Microbiology
Date: 15-06-2012
DOI: 10.1128/JVI.07133-11
Abstract: An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve in iduals with early ( n = 88) and chronic ( n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection ( R = −0.2 P = 0.003) however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF 114–121 ) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ∼35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.
Publisher: Springer Science and Business Media LLC
Date: 09-2017
DOI: 10.1038/NATURE23896
Abstract: This corrects the article DOI: 10.1038/nature22815.
Publisher: Wiley
Date: 07-2003
DOI: 10.1046/J.1468-1293.2003.00152.X
Abstract: To assess the prevalence and risk factors for HBV and HCV coinfection in the Australia HIV Observational Database (AHOD), and examine outcomes of HIV disease following initiation of highly active antiretroviral therapy (HAART). Analyses were based on 2086 participants recruited to AHOD by September 2002. Of these, 1605 (77%) had been tested for HBV surface antigen, 1704 (82%) for anti-HCV antibody and 1453 (70%) for both. Demographic and clinical predictors of HBV and HCV coinfection were examined. The impact of HBV and HCV coinfection on HIV disease progression was assessed by Kaplan-Meier survival curves and Cox proportional hazard model of time to AIDS events and death. Among those tested, prevalence of HBV surface antigen and HCV antibody were 6.3% and 13.1%, respectively (4.8% and 10.7%, respectively, among the entire cohort). In multivariate analyses, the only independent risk factor for HIV/HBV coinfection was coinfection with HCV. Independent risk factors for HIV/HCV coinfection were HIV exposure category (with people who reported injecting drug use [MSM & IDU, IDU only] or receipt of blood or blood products at markedly increased risk) and HBV coinfection. HIV disease outcomes following first initiation of a HAART regimen were similar for HIV/HBV and HIV/HCV coinfected patients compared with HIV-only patients in terms of AIDS-free survival and detectable HIV virus during the first 12 months. However, patients coinfected with HIV/HCV appeared to have a poorer response to HAART in terms of CD4 count changes, with a CD4 count increase of 32 cells/microL (95% CI 1-67) less than HIV-only patients. Coinfection with HBV or HCV is relatively common among HIV-infected participants in AHOD. HIV disease outcomes following HAART do not appear to be adversely affected by HBV/HCV coinfection, except for slightly poorer CD4 count responses in HIV/HCV coinfected patients.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Future Medicine Ltd
Date: 07-2010
DOI: 10.2217/PGS.10.77
Abstract: Drug hypersensitivity reactions and severe cutaneous adverse drug reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, are ex les of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that could traditionally not have been predicted based on the pharmacological characteristics of the drug alone. The discovery of new associations between these syndromes and specific HLA has created the promise that risk for these reactions could be predicted through pharmacogenetic screening, thereby avoiding serious morbidity and mortality associated with these types of drug reactions. Despite this, several hurdles exist in the translation of these associations into pharmacogenetic tests that could be routinely used in the clinical setting. HLA-B*5701 screening to prevent abacavir hypersensitivity syndrome is an ex le of a test now in widespread routine clinical use in the developed world.
Publisher: Elsevier BV
Date: 07-2016
Publisher: Oxford University Press (OUP)
Date: 13-02-2020
Abstract: A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in the general population. Given the broad changes in adaptive immunity, including memory T-cell expansion, and rising prevalence of diabetes in the human immunodeficiency virus (HIV) population, we assessed whether similar relationships were present in persons with HIV (PWH). Multiple CD4+ and CD8+ T-cell subsets were measured by flow cytometry, and prevalent diabetes cases were adjudicated by 2 physicians for PWH and HIV-negative participants in the Veterans Aging Cohort Study. Multivariable logistic regression models evaluated the association of T-cell subsets and diabetes stratified by HIV status, adjusted for cytomegalovirus serostatus and traditional risk factors. Among 2385 participants (65% PWH, 95% male, 68% African American), higher CD45RO+ memory CD4+ T cells and lower CD38+ CD4+ T cells were associated with prevalent diabetes, and had a similar effect size, in both the PWH and HIV-negative (P ≤ .05 for all). Lower CD38+CD8+ T cells were also associated with diabetes in both groups. The CD4+ and CD8+ T-cell subsets associated with diabetes are similar in PWH and HIV-negative in iduals, suggesting that diabetes in PWH may be related to chronic immune activation.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477967.V1
Abstract: Supplementary Figure 6: Neither time of s le nor institution drive significant gene expression changes.
Publisher: Cold Spring Harbor Laboratory
Date: 20-08-2021
DOI: 10.1101/2021.08.20.457054
Abstract: The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated immune responses in adult in iduals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis ( Mtb )-derived peptide pool. Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2003
DOI: 10.1097/00002030-200306130-00007
Abstract: Nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy provides sufficient conditions for progressive subcutaneous fat wasting in HIV-infected patients. As NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion, determinants of cellular mtDNA copy number and mitochondrial mass in adipocyte s les from NRTI-treated HIV-infected patients and antiretroviral-naive controls were investigated. Adipose tissue morphology was also assessed. Subcutaneous fat s les were obtained from NRTI-treated, HIV-infected patients (n = 21), antiretroviral therapy-naive HIV-infected controls (n = 11), and HIV-seronegative controls (n = 6). Non-adipocytes were removed by collagenase digestion. Adipocyte mtDNA copies/cell was measured using a real time PCR-based assay, and adipocyte mitochondrial protein content was also measured. Light and electron microscopy were performed on tissue s les. Adipocyte mtDNA copies/cell values were similar (P = 0.56) in HIV seronegative and HIV-infected control groups. NRTI treatment was associated with reduced adipocyte mtDNA copies/cell, representing mean mtDNA depletion in NRTI-treated in iduals of 77.7% compared with the mean value for the HIV-infected control group (P < 0001). Additionally, significant differences were found in adipocyte mtDNA copies/cell between patients receiving stavudine (n = 12, mean mtDNA depletion 87.1%) and zidovudine (n = 9, mean mtDNA depletion 52.1%) (P < 0.001). Adipocyte mitochondrial mass was increased in the stavudine group only (mean increase 289%, P < 0.01). NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting. Morphologic assessment also supports a role for NRTI therapy in inducing adipocyte metabolic dysfunction and cell death.
Publisher: American Thoracic Society
Date: 05-2019
DOI: 10.1164/AJRCCM-CONFERENCE.2019.199.1_MEETINGABSTRACTS.A6072
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2020
DOI: 10.1158/1538-7445.SABCS19-P3-08-15
Abstract: The recent approval of anti-PD-L1 immunotherapy in combination with nAB-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor-immune microenvironment (TIME). Patients with TNBC are routinely treated with neoadjuvant chemotherapy (NAC). Stromal tumor-infiltrating lymphocytes (sTILs) in the pre-treatment diagnostic biopsy are predictive of pathologic complete response (pCR). In patients with residual disease (RD) at surgery, sTILs confer good prognosis. However, the effect of chemotherapy on sTILs and how it influences the TIME are poorly understood. We examined immune-gene expression patterns before and after NAC in a series of 83 breast tumors, including 44 TNBCs, from patients with RD. sTILs were enumerated by standardized guidelines. Gene expression patterns were tested for association with recurrence-free (RFS) and overall survival (OS). T cell receptor sequencing (TCRseq) was performed on a subset (n=15) of tumors. In 4 patients undergoing NAC, PD-1-high and -negative CD8+ peripheral blood mononuclear cells (PBMCs) were profiled using single-cell RNAseq and multiplexed cytokine secretion assays. Post-NAC sTILs (≥30%) were only predictive of outcome (RFS p=0.019 OS p=0.05) in TNBC patients, but not in non-TNBC patients (RFS p=0.28 OS p=0.78) confirming that the prognostic capacity of sTILs is confined to TNBC. Pre-NAC sTILs were not predictive of outcome in either group, likely due to exclusion of patients experiencing pCR. The change in sTILs during NAC did not prognosticate outcome in TNBC, suggesting that in the post-NAC setting, only the most proximal measurement of sTILs is meaningful. However, these results did suggest that NAC alters the TIME. To examine the interplay among NAC, the TIME, and clinical outcomes, we tested the change in expression of 770 immune-related genes during NAC in univariate cox-proportional hazards models. In non-TNBC, no change in expression of any single gene was associated with RFS or OS at a false-discovery rate (FDR) of 10%. In TNBC, in idual changes in 12 genes and 204 genes were identified as associated with RFS and OS, respectively (FDR& %). Interestingly, in nearly all cases, upregulation of these genes during NAC was associated with improved outcome, with only 1 and 15 genes being associated with poor RFS and OS, respectively. Collapsing genes to functional and cell-type specific signatures gave similar insights: T cell, NK cell, TNF-superfamily, and toll-like receptor signatures were highly prognostic. Surprisingly, NAC did not alter T cell clonality in TNBC. Thus, the immunologic impact of chemotherapy appears to be specific to TNBC and is primarily a beneficial effect but does not appear to appreciably expand the clonality of tumor-infiltrating T cells. Using fresh PD-1HI CD8+ T cells isolated from PBMCs of patients undergoing NAC, we detected a significant increase in cytolytic and inflammatory cytokines secreted in 2 TNBC patients after chemotherapy, but not in 2 non-TNBC patients, which was particularly dramatic in one TNBC patient who experienced a pCR. A further characterization of PD-1HI CD8+ cells by single-cell RNAseq identified a sizeable expansion of cytolytic gene (granulysin, Ksp37, granzyme) expressing cells in the TNBC patient with pCR compared to the TNBC patient with RD. In conclusion, we have characterized the effects of NAC on the TIME. TNBC appears to be uniquely sensitive to the immunologic effects of NAC, and most of these effects are primarily stimulatory, rather than repressive. Finally, these changes can be observed in the PD-1HI CD8+ peripheral T cell compartment and appeared to co-occur with pCR. Citation Format: Justin M Balko, Mellissa Nixon, Paula I Gonzalez-Ericsson, Mark A Pilkinton, Wyatt J McDonnell, Violeta Sanchez, Susan R Opalenik, Sherene Loi, Brent Rexer, Vandana Abramson, Valerie Jansen, Simon Mallal, Jonathan D Marotti, Kevin Shee, Todd W Miller, Melinda E Sanders, Ingrid A Mayer, Roberto Salgado. Immunologic correlates of long-term outcome in the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium 2019 Dec 10-14 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2020 (4 Suppl):Abstract nr P3-08-15.
Publisher: SAGE Publications
Date: 08-2004
DOI: 10.1177/135965350400900609
Abstract: The availability of durable, effective antiretroviral therapy for HIV-infected patients has fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic acidosis, neuropathy, pancreatitis and, more recently, a syndrome of pathological loss of subcutaneous fat tissue (lipoatrophy). Importantly, the toxicity profile of each NRTI drug within this class is unique in terms of the overall risk of long-term complications, as well as the tissue specificity of its toxic effects. In this review, the clinical manifestations, risk factors and pathological basis for NRTI-associated toxicity syndromes are explored, with an emphasis on clinical assessment and management.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
DOI: 10.1038/NATURE03113
Abstract: The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/JVI.02147-16
Abstract: Dengue virus (DENV) is responsible for growing numbers of infections worldwide and has proven to be a significant challenge for vaccine development. We previously demonstrated that CD8 + T cell responses elicited by a dengue live attenuated virus (DLAV) vaccine resemble those observed after natural infection. In this study, we screened peripheral blood mononuclear cells (PBMCs) from donors vaccinated with a tetravalent DLAV vaccine (TV005) with pools of dengue virus-derived predicted major histocompatibility complex (MHC) class II binding peptides. The definition of CD4 + T cell responses after live vaccination is important because CD4 + T cells are known contributors to host immunity, including cytokine production, help for CD8 + T and B cells, and direct cytotoxicity against infected cells. While responses to all antigens were observed, DENV-specific CD4 + T cells were focused predominantly on the capsid and nonstructural NS3 and NS5 antigens. Importantly, CD4 + T cell responses in vaccinees were similar in magnitude and breadth to those after natural infection, recognized the same antigen hierarchy, and had similar profiles of HLA restriction. We conclude that TV005 vaccination has the capacity to elicit CD4 + cell responses closely mirroring those observed in a population associated with natural immunity. IMPORTANCE The development of effective vaccination strategies against dengue virus infection is of high global public health interest. Here we study the CD4 T cell responses elicited by a tetravalent live attenuated dengue vaccine and show that they resemble responses seen in humans naturally exposed to dengue virus. This is an important issue, since it is likely that optimal immunity induced by a vaccine requires induction of CD4 + responses against the same antigens as those recognized as dominant in natural infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection against dengue virus.
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2020
DOI: 10.1101/2020.07.28.221325
Abstract: Chronic innate and adaptive immune activation may contribute to high prevalence of cardiovascular disease in persons living with HIV (PLWH). We assessed coronary plaques from deceased PLWH (n=6) and HIV-negative (n=6) persons matched by age and gender. Formalin-fixed, paraffin-embedded 5μm thick sections were processed using Movat, hematoxylin and eosin, immunohistochemical and immunofluorescence stains. Immune cell populations were measured using surface antibodies, and immune-related protein expression from macrophage rich, T-cell rich and perivascular adipose tissue regions using GeoMx ® digital spatial profiling. Coronary plaques from PLWH and HIV-negative persons had similar plaque area and percent stenosis. Percent CD163 + cells as measured by immunohistochemical staining was significantly higher in PLWH, median 0.29% (IQR 0.11-0.90) vs. 0.01% (IQR 0.0013-0.11) in HIV-negative plaque, p = 0.02 (Figure 1A). Other surface markers of innate cells (CD68 + , p=0.18), adaptive immune cells (CD3 + , p=0.39 CD4 + , p=0.09 CD8 + , p=0.18) and immune trafficking markers (CX3CR1 + , p=0.09) within the coronary plaque trended higher in HIV-positive plaques but did not reach statistical significance. GeoMx ® digital spatial profiling showed higher differential protein expression of CD163 (scavenger receptor for hemoglobin-haptoglobin complex), stimulator of interferon gamma (STING, a cytosolic DNA sensor), CD25 and granzyme-B in the HIV-positive compared to HIV-negative, p .05(Figure 1B). Increased inflammation within the coronary plaques of PLWH is characterized by more innate and adaptive immune cells. Higher STING expression in PLWH suggests that immune response to viral antigens within the plaque might be a driver above other stimulants. STING inhibitors are available and could be investigated as a future therapeutic target in PWH if these results are replicated with a larger number of plaques. Immunohistochemical and fluorescent stains combined with GeoMx ® digital spatial profiling allowed for deep characterization of immune cells within intact coronary plaques and perivascular adipose tissue Coronary plaques from HIV-positive persons had higher proportion of CD163 + immune cells compared to HIV-negative persons Differential protein expression of immune-rich regions of interest within intact 5μm sections of coronary plaques revealed higher levels of stimulator of interferon gamma (STING) in HIV-positive persons
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-03-2005
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2013
Abstract: Multiple genome-wide association studies have revealed that human leukocyte antigen (HLA) genes of the major histocompatibility complex locus have the strongest impact on HIV. In particular, a single-nucleotide polymorphism 35 base pairs upstream of HLA-C shows significant association with viral load and protection against HIV. How HLA-C mediates these effects is unknown. Apps et al. (p. 87 ) now demonstrate that increasing surface expression of HLA-C is associated with reduced viral load and reduced rate of progression to low CD4 + T cell counts in African and European Americans. High HLA-C expression likely promoted improved HIV control through a more effective cytotoxic CD8 + T cell response. In contrast to HIV infection, high HLA-C expression was associated with a higher risk of the inflammatory bowel disease, Crohn's disease.
Publisher: Cold Spring Harbor Laboratory
Date: 11-04-2020
DOI: 10.1101/2020.04.10.029454
Abstract: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host’s anti-viral immune response, in turn affecting the frequency of variants over-time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. Deep sequencing data of SARS-CoV-2 from public databases and from clinical s les were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Sequence analysis suggests that the three adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence (CS) of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep sequencing data from 981 clinical s les confirmed the presence of the novel TRS-CS-dimerization domain RNA in in iduals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans resulting in both coding changes and novel sub-genomic RNA transcripts suggests this as a mechanism for ersification and adaptation within its new host.
Publisher: The American Association of Immunologists
Date: 15-06-2005
DOI: 10.4049/JIMMUNOL.174.12.7524
Abstract: Mutational escape from the CTL response represents a major driving force for viral ersification in HIV-1-infected adults, but escape during infancy has not been described previously. We studied the immune response of perinatally infected children to an epitope (B57-TW10) that is targeted early during acute HIV-1 infection in adults expressing HLA-B57 and rapidly mutates under this selection pressure. Viral sequencing revealed the universal presence of escape mutations within TW10 among B57- and B5801-positive children. Mutations in TW10 and other B57-restricted epitopes arose early following perinatal infection of B57-positive children born to B57-negative mothers. Surprisingly, the majority of B57/5801-positive children exhibited a robust response to the TW10 escape variant while recognizing the wild-type epitope weakly or not at all. These data demonstrate that children, even during the first years of life, are able to mount functional immune responses of sufficient potency to drive immune escape. Moreover, our data suggest that the consequences of immune escape may differ during infancy because most children mount a strong variant-specific immune response following escape, which is rarely seen in adults. Taken together, these findings indicate that the developing immune system of children may exhibit greater plasticity in responding to a continually evolving chronic viral infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2003
Publisher: Elsevier BV
Date: 2018
Publisher: Wiley
Date: 30-06-2020
DOI: 10.1002/LARY.28840
Publisher: Oxford University Press (OUP)
Date: 09-09-2013
Publisher: PeerJ
Date: 18-05-2018
DOI: 10.7717/PEERJ.4803
Abstract: Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori -infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e −5 , which is similar to the rates detected previously in H. pylori- infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions ( fur , tonB1 , fecA2 , fecA3 , and frpB3 ) or encoding outer membrane proteins ( alpA, oipA, fecA2, fecA3, frpB3 and cagY ). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model.
Publisher: American Society for Microbiology
Date: 03-2014
DOI: 10.1128/JVI.03014-13
Abstract: HIV-1 infection is characterized by the rapid generation of genetic ersity that facilitates viral escape from immune selection and antiretroviral therapy. Despite recombination's crucial role in viral ersity and evolution, little is known about the genomic factors that influence recombination between highly similar genomes. In this study, we use a minimally modified full-length HIV-1 genome and high-throughput sequence analysis to study recombination in gag and pol in T cells. We find that recombination is favored at a number of recombination hot spots, where recombination occurs six times more frequently than at corresponding cold spots. Interestingly, these hot spots occur near important features of the HIV-1 genome but do not occur at sites immediately around protease inhibitor or reverse transcriptase inhibitor drug resistance mutations. We show that the recombination hot and cold spots are consistent across five blood donors and are independent of coreceptor-mediated entry. Finally, we check common experimental confounders and find that these are not driving the location of recombination hot spots. This is the first study to identify the location of recombination hot spots between two similar viral genomes with great statistical power and under conditions that closely reflect natural recombination events among HIV-1 quasispecies. IMPORTANCE The ability of HIV-1 to evade the immune system and antiretroviral therapy depends on genetic ersity within the viral quasispecies. Retroviral recombination is an important mechanism that helps to generate and maintain this genetic ersity, but little is known about how recombination rates vary within the HIV-1 genome. We measured recombination rates in gag and pol and identified recombination hot and cold spots, demonstrating that recombination is not random but depends on the underlying gene sequence. The strength and location of these recombination hot and cold spots can be used to improve models of viral dynamics and evolution, which will be useful for the design of robust antiretroviral therapies.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2009
Publisher: Elsevier BV
Date: 12-2015
Publisher: American Society for Clinical Investigation
Date: 18-03-2019
DOI: 10.1172/JCI123726
Publisher: The American Association of Immunologists
Date: 09-2011
Abstract: Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 in iduals from the same cohort, which gave rise to 874 HLA–HIV associations in genetic analyses, taking into account autologous viral sequences and in idual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-γ responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA–HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for ersity coverage approaches in HIV vaccine design.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2020
DOI: 10.1038/S41467-020-15626-W
Abstract: A diagnosis of motor Parkinson’s disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis.
Publisher: Oxford University Press (OUP)
Date: 22-02-2007
DOI: 10.1093/JAC/DKL557
Abstract: The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.
Publisher: Frontiers Media SA
Date: 26-10-2021
DOI: 10.3389/FIMMU.2021.746986
Abstract: Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. Another described, but less understood, adaptation strategy involves the selection of mutations within epitopes that retain immune recognition, suggesting a benefit for the virus despite continued immune pressure (termed non-classical adaptation). To understand this adaptation strategy, we utilized a single cell transcriptomic approach to identify features of the HIV-specific CD8 + T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes containing a non-classical adaptation. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8 + T cells of chronic (n=7) and acute (n=4) HIV-infected subjects identified by either HLA class I tetramers or upregulation of activation markers following peptide stimulation. CD8 + T cells were predominantly dual tetramer + , confirming a large proportion of cross-reactive TCR clonotypes capable of recognizing the NAE and AE form. However, single-reactive CD8 + T cells were identified in acute HIV-infected subjects only, providing the potential for the selection of T cell clones over time. The transcriptomic profile of CD8 + T cells was dependent on the autologous virus: subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an ‘effective’ immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNɣ, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8 + T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.
Publisher: Informa UK Limited
Date: 08-2013
DOI: 10.1310/HCT1404-160
Abstract: Rapid screening for the detection of HLA-B*57:01 in the prevention of abacavir hypersensitivity in HIV-1-infected patients is a hallmark for clinical services. The aim of this work was to analyze the utility of flow cytometry with a new FITC-conjugated B-17 monoclonal antibody (mAb3E12) for HLA-B*57:01 screening in a Spanish cohort of 577 HIV-1+ in iduals. Cryopreserved peripheral blood mononuclear cell s les from HIV-1+ in iduals were analyzed by flow cytometry with the mAb 3E12 that recognizes both HLA-B*57 and HLA-B*58 alleles (members of the group specificity, HLA-B17). Patients' DNA s les had been previously typed for HLA-B*57:01 with PCR-SSO or PCR-SSP and additional DNA sequencing (EPI Study). The results obtained by flow cytometry were compared with the results obtained by the DNA-PCR techniques. By flow cytometry, 46 s les (7.97%) were positive for HLA-B17, 530 (91.86%) were negative, and 1 (0.17%) was undetermined. All s les found negative by flow cytometry were negative for HLA-B*57:01 by DNA-PCR. Of the HLA-B17 positive s les, 31 (67.4%) were positive for HLA-B*57:01, 2 (3.25%) were positive for HLA-B*57:03, 11 (26.1%) were positive for HLA-B*58, and 2 (3.25%) were negative for both HLA-B*57 and HLA-B*58 antigens. The undetermined s le was negative for HLA-B*57 and HLA-B*58 alleles by DNA-PCR. This study shows that flow cytometry with mAb3E12 is a highly sensitive method (no false negatives) to implement prior to DNA-PCR analysis for rapid screening of HLA-B*57:01. Additional confirmation by molecular HLA typing method would be required in less than 10% of the cohort of HIV-1-infected in iduals.
Publisher: Cold Spring Harbor Laboratory
Date: 23-03-2022
DOI: 10.1101/2022.03.21.484794
Abstract: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. We generated a comprehensive SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH with a spectrum of metabolic health. Glucose intolerance was associated with increased lipid-associated macrophages and CD4 + and CD8 + T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4 + effector memory tissue resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Many of these findings were present in a separate group of 32 diabetic HIV-negative persons, suggesting these changes are not specific to HIV.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2001
Publisher: Elsevier BV
Date: 02-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
Publisher: Elsevier BV
Date: 03-2011
Publisher: Wiley
Date: 10-10-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1997
DOI: 10.1097/00042560-199709010-00006
Abstract: To assess time trends in incidence of AIDS illnesses in Australia, a retrospective cohort of people diagnosed with AIDS from January 1, 1983 to December 31, 1994 in three HIV medicine units in Sydney, Melbourne, and Perth was established. Data on initial and subsequent AIDS illnesses were available for 2580 AIDS cases, or 45% of Australian AIDS notifications over the study period. Males represented 97.2% of the cohort, and HIV exposure category was homosexual contact for 89.9%. Subcohorts were formed by interval of AIDS diagnosis: 1983 through 1987, 1988 through 1990, and 1991 through 1994, with estimation of cumulative risk for each AIDS illness by the Kaplan-Meier method. The cumulative risk declined for Pneumocystis carinii pneumonia (PCP) (p < 0.0001) and for Kaposi's sarcoma (KS) (p < 0.0001) PCP cumulative risk estimates 2 years following AIDS diagnosis were 70% for people diagnosed with AIDS in 1983 through 1987 and 48% in 1991 through 1994, and KS cumulative risk estimates 2 years following AIDS diagnosis were 44% in 1983 through 1987 and 32% in 1991 through 1994. In contrast, cumulative risk increased from 34% to 40% for cytomegalovirus (CMV) disease (p = 0.005), from 47% to 50% for Mycobacterium avium complex (MAC) (p < 0.0001), and from 26% to 33% for esophageal candidiasis (p < 0.0001). Corresponding to this changing spectrum of AIDS illness has been an increase in severity of immunodeficiency at AIDS, with median CD4 cell count declining from 54 cells/mm3 in 1983 through 1987 to 34/mm3 in 1991 through 1994 (p = 0.002).
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/SH11085
Abstract: Self-report questionnaires on alcohol, nicotine and other drugs were administered to assess the current prevalence of alcohol, drug and nicotine use in our tertiary HIV service and inform the establishment of effective interventions. Many respondents reported use of alcohol over the preceding month (111 out of 152, 73%), and recent drug use (48 out of 137, 35%) and frequently both. Sessional alcohol consumption was prevalent among drinkers (52 out of 111, 47%), and correlated with both early treatment phase (P = 0.009) and non-adherence (P = 0.03). Encouraged by a notable proportion of patients expressing interest in clinic-based smoking cessation counselling, we recommend a targeted education strategy to motivate patients in health-seeking behaviours.
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3835595
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478018.V1
Abstract: Supplementary Tables
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1086/367849
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22477961.V1
Abstract: Supplementary Figure 8: Changes in immune-related genes in response to NAC are not associated with outcome in ER+ or HER2+ tumors with residual disease.
Publisher: Public Library of Science (PLoS)
Date: 25-07-2013
Location: United States of America
No related grants have been discovered for Simon Mallal.