ORCID Profile
0000-0003-4307-9161
Current Organisation
University of Oxford
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Society for Microbiology
Date: 02-2010
DOI: 10.1128/JVI.01499-09
Abstract: Hepatitis C virus (HCV)-specific CD8 + T cells in persistent HCV infection are low in frequency and paradoxically show a phenotype associated with controlled infections, expressing the memory marker CD127. We addressed to what extent this phenotype is dependent on the presence of cognate antigen. We analyzed virus-specific responses in acute and chronic HCV infections and sequenced autologous virus. We show that CD127 expression is associated with decreased antigenic stimulation after either viral clearance or viral variation. Our data indicate that most CD8 T-cell responses in chronic HCV infection do not target the circulating virus and that the appearance of HCV-specific CD127 + T cells is driven by viral variation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
Publisher: American Society for Microbiology
Date: 15-11-2009
DOI: 10.1128/JVI.00884-09
Abstract: Hepatitis C virus subtype 3a is a highly prevalent and globally distributed strain that is often associated with infection via injection drug use. This subtype exhibits particular phenotypic characteristics. In spite of this, detailed genetic analysis of this subtype has rarely been performed. We performed full-length viral sequence analysis in 18 patients with chronic HCV subtype 3a infection and assessed genomic viral variability in comparison to other HCV subtypes. Two novel regions of intragenotypic hypervariability within the envelope protein E2, of HCV genotype 3a, were identified. We named these regions HVR495 and HVR575. They consisted of flanking conserved hydrophobic amino acids and central variable residues. A 5-amino-acid insertion found only in genotype 3a and a putative glycosylation site is contained within HVR575. Evolutionary analysis of E2 showed that positively selected sites within genotype 3a infection were largely restricted to HVR1, HVR495, and HVR575. Further analysis of clonal viral populations within single hosts showed that viral variation within HVR495 and HVR575 were subject to intrahost positive selecting forces. Longitudinal analysis of four patients with acute HCV subtype 3a infection s led at multiple time points showed that positively selected mutations within HVR495 and HVR575 arose early during primary infection. HVR495 and HVR575 were not present in HCV subtypes 1a, 1b, 2a, or 6a. Some variability that was not subject to positive selection was present in subtype 4a HVR575. Further defining the functional significance of these regions may have important implications for genotype 3a E2 virus-receptor interactions and for vaccine studies that aim to induce cross-reactive anti-E2 antibodies.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1053/J.GASTRO.2021.05.059
Abstract: Barrett's epithelium measurement using widely accepted Prague C&M classification is highly operator dependent. We propose a novel methodology for measuring this risk score automatically. The method also enables quantification of the area of Barrett's epithelium (BEA) and islands, which was not possible before. Furthermore, it allows 3-dimensional (3D) reconstruction of the esophageal surface, enabling interactive 3D visualization. We aimed to assess the accuracy of the proposed artificial intelligence system on both phantom and endoscopic patient data. Using advanced deep learning, a depth estimator network is used to predict endoscope camera distance from the gastric folds. By segmenting BEA and gastroesophageal junction and projecting them to the estimated mm distances, we measure C&M scores including the BEA. The derived endoscopy artificial intelligence system was tested on a purpose-built 3D printed esophagus phantom with varying BEAs and on 194 high-definition videos from 131 patients with C&M values scored by expert endoscopists. Endoscopic phantom video data demonstrated a 97.2% accuracy with a marginal ± 0.9 mm average deviation for C&M and island measurements, while for BEA we achieved 98.4% accuracy with only ±0.4 cm The proposed methodology automatically extracts Prague C&M scores with high accuracy. Quantification and 3D reconstruction of the entire Barrett's area provides new opportunities for risk stratification and assessment of therapy response.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2018
DOI: 10.1038/S41467-018-07207-9
Abstract: Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1 −/− mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2 −/− γC −/− mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.
Publisher: American Society for Microbiology
Date: 04-2004
DOI: 10.1128/JVI.78.7.3447-3454.2004
Abstract: Hepatitis C virus (HCV) persists in the majority of those infected despite host immune responses. Evidence has accrued that selectively fixed mutations in the envelope genes (E1 and E2) are associated with viral persistence, particularly those that occur within the first hypervariable region of E2 (HVR1). However, the in idual amino acid residues under selection have not been identified, nor have their selection pressures been measured, despite the importance of this information for understanding disease pathogenesis and for vaccine design. We performed a high-resolution analysis of published gene sequence data from in iduals undergoing acute HCV infection, employing two phylogenetic methods to determine site-specific selection pressures. Strikingly, we found a statistically significant association between the number of sites selected and disease outcome, with the fewest selected sites in fulminant HCV cases and the greatest number of selected sites in rapid progressors, reflecting the duration and intensity of the arms race between host and virus. Moreover, sites outside the HVR1 appear to play a major role in viral evolution and pathogenesis, although there was no association between viral persistence and specific mutations in E1 and E2. Our analysis therefore allows fine dissection of immune selection pressures, which may be more erse than previously thought. Such analyses could play a similarly informative role in studies of other persistent virus infections, such as human immunodeficiency virus.
Publisher: BMJ
Date: 19-06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-05-2022
DOI: 10.1002/HEP.32470
Abstract: A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization elimination targets. Neutralizing antibodies (nAbs) and CD4 We show that vaccinating with ChAd-Gt1-6 and E2Δ123 These data are an important step forward for the development of a pan-genotype HCV vaccine to elicit T cells and nAbs for future assessment in humans.
Publisher: American Society for Microbiology
Date: 15-09-2005
DOI: 10.1128/JVI.79.18.12100-12105.2005
Abstract: The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2017
DOI: 10.1038/NG.3835
Publisher: Elsevier BV
Date: 03-2021
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: Elsevier BV
Date: 12-2020
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: Springer Science and Business Media LLC
Date: 11-12-2021
DOI: 10.1038/S41586-020-03065-Y
Abstract: Host-mediated lung inflammation is present
Publisher: Public Library of Science (PLoS)
Date: 14-12-2010
Publisher: eLife Sciences Publications, Ltd
Date: 25-06-2019
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41590-021-01084-Z
Abstract: NP 105–113 -B*07:02-specific CD8 + T cell responses are considered among the most dominant in SARS-CoV-2-infected in iduals. We found strong association of this response with mild disease. Analysis of NP 105–113 -B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP 105–113 -B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP 105–113 -B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP 105–113 -B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
Publisher: Oxford University Press (OUP)
Date: 19-08-2020
DOI: 10.1111/CEI.13502
Abstract: The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg, reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.
Publisher: American Society of Hematology
Date: 06-2006
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-01-2021
Abstract: Mucosal-associated invariant T (MAIT) cells are a T cell subset important for mucosal homeostasis. These cells recognize derivatives of microbiota-derived vitamin B2 precursors but can also be activated by certain cytokines in the context of viral infections. Provine et al. report that a leading adenoviral vector vaccine, ChAdOx1, activated MAIT cells in immunized mice (see the Perspective by Juno and O'Connor). This activation required interferon-α produced by plasmacytoid dendritic cells as well as monocyte-derived interleukin-18 and tumor necrosis factor. MAIT cell activation positively correlated with vaccine-mediated T cell responses in human subjects, and mice deficient in MAIT cells showed impaired CD8 + T cell immunity to target antigens after vaccination. This work suggests an additional pathway that could be exploited to enhance the efficacy of vaccines. Science , this issue p. 521 see also p. 460
Publisher: Rockefeller University Press
Date: 20-12-2004
DOI: 10.1084/JEM.20041006
Abstract: In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70–80% of in iduals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8–restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon γ enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8–associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2018
DOI: 10.1002/HEP.29877
Abstract: New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16‐week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 ( IFNL4 ) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon‐stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non‐CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (H epatology 2018 00:000‐000).
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
Publisher: American Society for Microbiology
Date: 02-2003
DOI: 10.1128/JVI.77.3.2251-2257.2003
Abstract: Natural killer T (NKT) cells are thought to be involved in innate responses against infection. We investigated one specific type of NKT cell, Vα24/Vβ11 double positive, in hepatitis C virus (HCV) infection. Lower frequencies of this population were detected in the blood of HCV PCR-positive patients than in controls. Unlike Vα24/Vβ11 NKT cells found in blood, those in the liver appeared to be recently activated.
Publisher: American Society for Microbiology
Date: 02-2010
DOI: 10.1128/JVI.02512-09
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Publisher: Wiley
Date: 06-01-2021
DOI: 10.1002/PATH.5592
Publisher: The American Association of Immunologists
Date: 02-2004
DOI: 10.4049/JIMMUNOL.172.3.1744
Abstract: Recent studies using MHC class I tetramers have shown that CD8+ T cell responses against different persistent viruses vary considerably in magnitude and phenotype. At one extreme, hepatitis C virus (HCV)-specific CD8+ T cell responses in blood are generally weak and have a phenotype that is perforin low and CCR7 high (early memory). At the other, specific responses to CMV are strong, perforin high, and CCR7 low (mature or effector memory). To examine the potential mechanisms behind this ersity, we compared CMV-specific responses in HCV-infected and healthy in iduals. We find a striking difference in the phenotype of CMV-specific CD8+ T cells between these groups. In the HCV-infected cohort, CMV-specific CD8+ T cells lost markers associated with maturity they had increased expression of CCR7 and reduced expression of Fas and perforin. They nevertheless responded to Ag in vitro in a manner similar to controls, with strong proliferation and appropriate acquisition of effector memory markers. The reduction in mature CD8 T cells in HCV-infected in iduals may arise through either impairment or regulation of T cell stimulation, or through the early loss of mature T cells. Whatever the mechanism, HCV has a pervasive influence on the circulating CD8+ T cell population, a novel feature that may be a hallmark of this infection.
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 06-2014
Publisher: Springer Science and Business Media LLC
Date: 09-02-2018
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
Publisher: American Society for Microbiology
Date: 07-2004
DOI: 10.1128/JVI.78.13.7284-7287.2004
Abstract: Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct “central memory” CD62L + phenotype.
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1046/J.1365-2249.2003.02033.X
Abstract: CD4+ T lymphocyte responses are thought to play a major role in control of the hepatitis C virus (HCV). Few, however, have been mapped down to the level of peptide and HLA restriction. Furthermore, the ability of such T cells to respond to viruses which differ in genotype has not been addressed in detail. In most cases of persistent infection with HCV, CD4 proliferative responses are weak or absent. From a large cohort of persistently infected patients, we identified an in idual with unusually robust and persistent responses in the face of chronic infection. We firstly mapped two peptide epitopes to regions of the nonstructural protein NS4 (aa1686–1705 and aa 1746–1765). However, in contrast to the genotype 1a derived antigens used for mapping, the infecting virus was identified as genotype 3a. Strikingly, the patient's CD4 response to these epitopes were specific only for the genotype 1a sequence, and did not recognize genotype 3a synthetic peptides. Serologic assays indicated that prior exposure to HCV of genotype 1 had occurred. This patient therefore maintains strong CD4 proliferative responses which are genotype specific and not cross-reactive. The apparent ‘misdirection’ of these nonprotective responses has important implications for the role of natural and vaccine induced CD4 responses in the face of variable viruses.
Publisher: Oxford University Press (OUP)
Date: 15-12-2017
Publisher: Public Library of Science (PLoS)
Date: 25-07-2007
Publisher: The Royal Society
Date: 29-08-2000
Abstract: Hepatitis C virus (HCV) infection is a major public health problem, affecting an estimated 3% of the world's population, and over 10% in some countries. Infection in most cases becomes persistent, and can lead to hepatic inflammation, fibrosis and liver failure. The T lymphocyte reponse, in particular that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involved in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide tetrameric complexes (tetramers) to study antiviral CTL responses has revolutionized our approach to the study of human infection. We have used a panel of MHC class I tetramers to analyse immune responses in HCV–infected in iduals at various stages of disease. We find that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms of lymphocyte number and function. A number of potential explanations for this ‘CTL failure’ are discussed.
Publisher: Springer Science and Business Media LLC
Date: 02-06-1994
DOI: 10.1038/369403A0
Abstract: Most asymptomatic in iduals infected with HIV-1 have a cytotoxic T lymphocyte (CTL) response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14). Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. But peptide variants of class I-restricted epitopes cause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the original epitope. This mirrors similar findings in class II-restricted systems. Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same in iduals. The effect is present if the epitopes are derived from synthetic peptides and when they are processed from full-length proteins expressed by either recombinant vaccinia constructs or replicating HIV.
Publisher: eLife Sciences Publications, Ltd
Date: 03-09-2019
DOI: 10.7554/ELIFE.42463
Abstract: Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV ersity IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.
Publisher: American Society for Microbiology
Date: 10-2016
DOI: 10.1128/JCM.00330-16
Abstract: Affordable next-generation sequencing (NGS) technologies for hepatitis C virus (HCV) may potentially identify both viral genotype and resistance genetic motifs in the era of directly acting antiviral (DAA) therapies. This study compared the ability of high-throughput NGS methods to generate full-length, deep, HCV sequence data sets and evaluated their utility for diagnostics and clinical assessment. NGS methods using (i) unselected HCV RNA (metagenomics), (ii) preenrichment of HCV RNA by probe capture, and (iii) HCV pre lification by PCR implemented in four United Kingdom centers were compared. Metrics of sequence coverage and depth, quasispecies ersity, and detection of DAA resistance-associated variants (RAVs), mixed HCV genotypes, and other coinfections were compared using a panel of s les with different viral loads, genotypes, and mixed HCV genotypes/subtypes [geno(sub)types]. Each NGS method generated near-complete genome sequences from more than 90% of s les. Enrichment methods and PCR pre lification generated greater sequence depth and were more effective for s les with low viral loads. All NGS methodologies accurately identified mixed HCV genotype infections. Consensus sequences generated by different NGS methods were generally concordant, and majority RAVs were consistently detected. However, methods differed in their ability to detect minor populations of RAVs. Metagenomic methods identified human pegivirus coinfections. NGS provided a rapid, inexpensive method for generating whole HCV genomes to define infecting genotypes, RAVs, comprehensive viral strain analysis, and quasispecies ersity. Enrichment methods are particularly suited for high-throughput analysis while providing the genotype and information on potential DAA resistance.
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2020
DOI: 10.1101/2020.07.17.20155218
Abstract: ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global participation has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report, our 17th report, is a part of a series published over the past 2 years. Data have been entered for 800,459 in iduals from 1701 partner institutions and networks across 60 countries. The comprehensive analyses detailed in this report includes hospitalised in iduals of all ages for whom data collection occurred between 30 January 2020 and up to and including 5 January 2022, AND who have laboratory-confirmed SARS-COV-2 infection or clinically diagnosed COVID-19. For the 699,014 cases who meet eligibility criteria for this report, selected findings include: median age of 58 years, with an approximately equal (50/50) male:female sex distribution 29% of the cohort are at least 70 years of age, whereas 4% are 0-19 years of age the most common symptom combination in this hospitalised cohort is shortness of breath, cough, and history of fever, which has remained constant over time the five most common symptoms at admission were shortness of breath, cough, history of fever, fatigue/malaise, and altered consciousness/confusion, which is unchanged from the previous reports age-associated differences in symptoms are evident, including the frequency of altered consciousness increasing with age, and fever, respiratory and constitutional symptoms being present mostly in those 40 years and above 16% of patients with relevant data available were admitted at some point during their illness into an intensive care unit (ICU), which is slightly lower than previously reported (19%) antibiotic agents were used in 35% of patients for whom relevant data are available (669,630), a significant reduction from our previous reports (80%) which reflects a shifting proportion of data contributed by different institutions in ICU/HDU admitted patients with data available (50,560), 91% received antibiotics use of corticosteroids was reported in 24% of all patients for whom data were available (677,012) in ICU/HDU admitted patients with data available (50,646), 69% received corticosteroids outcomes are known for 632,518 patients and the overall estimated case fatality ratio (CFR) is 23.9% (95%CI 23.8-24.1), rising to 37.1% (95%CI 36.8-37.4) for patients who were admitted to ICU/HDU, demonstrating worse outcomes in those with the most severe disease To access previous versions of ISARIC COVID-19 Clinical Data Report please use the link below: esearch/covid-19-clinical-research-resources/evidence-reports/
Publisher: BMJ
Date: 26-07-2010
Abstract: Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected in iduals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected in iduals by ex vivo interferon-gamma-ELISpot responses to HCV core peptides, that predominantly stimulate CD4(+) T cells. HCV RNA levels were assessed by real-time PCR in 114 in iduals. The proportion of in iduals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in in iduals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log(10) IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (-0.3 log10 IU/ml, p=0.02). Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected in iduals.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2023
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1038/S41385-019-0180-2
Abstract: Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell-T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + in iduals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one in idual. As previously shown for blood, CD32
Publisher: Cold Spring Harbor Laboratory
Date: 25-09-2020
DOI: 10.1101/2020.09.24.20200048
Abstract: The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs 1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. 2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. 3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org ) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing % of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 × 10 −12 ), within the gene encoding dipeptidyl peptidase 9 ( DPP9 ), at chr12q24.13 (rs10735079, p =1.65 × 10 −8 ) in a gene cluster encoding antiviral restriction enzyme activators ( OAS1, OAS2, OAS3 ), and at chr21q22.1 (rs2236757, p = 4.99 × 10 −8 ) in the interferon receptor gene IFNAR2 . Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 × 10 −30 ). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2 , and high expression of TYK2 , to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Publisher: Wiley
Date: 06-2004
Abstract: The frequency and phenotype of human antiviral memory CD8(+) T cells in blood are well studied, yet little is known about their distribution within tissues. Analysis of antiviral CD8(+) T cell populations derived from a unique set of normal liver and blood s les identified a consistent population of virus-specific cells within the liver. In comparison to the circulating T cells, the liver-derived T cells were present at frequencies which were variably enriched compared to that in the blood, and showed significant differences with regard to the expression of CD45RA, CD45RO, CD95, CCR7, CD27 and CD28. The differences in these cell surface markers are consistent with a mature 'effector memory' phenotype of antigen-specific CD8(+) T cells within the liver. An enrichment of an activated subset of NKT cells (V alpha 24/V beta 11) was also observed, a finding which may be relevant to the regulation of the antiviral populations.
Publisher: Elsevier
Date: 2020
Publisher: American Society for Microbiology
Date: 15-10-2005
DOI: 10.1128/JVI.79.20.12979-12988.2005
Abstract: Multispecific CD8 + T-cell responses are thought to be important for the control of acute hepatitis C virus (HCV) infection, but to date little information is actually available on the breadth of responses at early time points. Additionally, the influence of early therapy on these responses and their relationships to outcome are controversial. To investigate this issue, we performed comprehensive analysis of the breadth and frequencies of virus-specific CD8 + T-cell responses on the single epitope level in eight acutely infected in iduals who were all started on early therapy. During the acute phase, responses against up to five peptides were identified. During therapy, CD8 + T-cell responses decreased rather than increased as virus was controlled, and no new specificities emerged. A sustained virological response following completion of treatment was independent of CD8 + T-cell responses, as well as CD4 + T-cell responses. Rapid recrudescence also occurred despite broad CD8 + T-cell responses. Importantly, in vivo suppression of CD3 + T cells using OKT3 in one subject did not result in recurrence of viremia. These data suggest that broad CD8 + T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses.
Publisher: Cold Spring Harbor Laboratory
Date: 18-12-2017
DOI: 10.1101/236083
Abstract: ABSTRACT Human herpes virus 6 (HHV-6) is a ubiquitous organism that can cause a variety of clinical syndromes ranging from short-lived rash and fever through to life-threatening encephalitis. We set out to generate observational data regarding the epidemiology of HHV-6 infection in clinical s les from a UK teaching hospital and to compare different diagnostic approaches. First, we scrutinized HHV-6 detection in s les submitted to our hospital laboratory through routine diagnostic pathways. Second, we undertook a pilot study using Illumina next generation sequencing (NGS) to determine the frequency of HHV-6 in CSF and respiratory s les that were initially submitted to the laboratory for other diagnostic tests. Of 72 s les tested for HHV-6 by PCR at the request of a clinician, 24 (33%) were positive for HHV-6. The majority of these patients were under the care of the haematology team (30/41, 73%), and there was a borderline association between HHV-6 detection and both Graft versus Host Disease (GvHD) and Central nervous system (CNS) disease (p=0.05 in each case). We confirmed detection of HHV-6 DNA using NGS in 4/20 (20%) CSF and respiratory s les. HHV-6 is common in clinical s les submitted from a high-risk haematology population, and enhanced screening of this group should be considered. NGS can be used to identify HHV-6 from a complex microbiomee, but further controls are required to define the sensitivity and specificity, and to correlate these results with clinical disease. Our results underpin ongoing efforts to develop NGS technology for viral diagnostics.
Publisher: Wiley
Date: 20-07-2006
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1038/MI.2017.74
Publisher: Elsevier BV
Date: 12-2020
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2020
DOI: 10.1101/2020.08.14.20168088
Abstract: Severe COVID-19 is characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied simple machine learning techniques to a large prospective cohort of hospitalised patients with COVID-19 identify clinically meaningful sub-groups. We obtained structured clinical data on 59 011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25 477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33 534 cases recruited to ISARIC-4C, and in 4 445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-groups. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were common, and a subgroup of patients reported few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom clusters were highly consistent in replication analysis using a further 35446 in iduals subsequently recruited to ISARIC-4C. Similar patterns were externally verified in 4445 patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication of patient clusters. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four patterns are usefully distinct from the core symptom groups: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms. These observations deepen our understanding of COVID-19 and will influence clinical diagnosis, risk prediction, and future mechanistic and clinical studies. Medical Research Council National Institute Health Research Well-come Trust Department for International Development Bill and Melinda Gates Foundation Liverpool Experimental Cancer Medicine Centre.
Publisher: F1000 Research Ltd
Date: 13-10-2015
DOI: 10.12688/F1000RESEARCH.7111.1
Abstract: The routine availability of high-depth virus sequence data would allow the sensitive detection of resistance-associated variants that can jeopardize HIV or hepatitis C virus (HCV) treatment. We introduce ve-SEQ, a high-throughput method for sequence-specific enrichment and characterization of whole-virus genomes at up to 20% ergence from a reference sequence and 1,000-fold greater sensitivity than direct sequencing. The extreme genetic ersity of HCV led us to implement an algorithm for the efficient design of panels of oligonucleotide probes to capture any sequence among a defined set of targets without detectable bias. ve-SEQ enables efficient detection and sequencing of any HCV genome, including mixtures and intra-host variants, in a single experiment, with greater tolerance of sequence ersity than standard lification methods and greater sensitivity than metagenomic sequencing, features that are directly applicable to other pathogens or arbitrary groups of target organisms, allowing the combination of sensitive detection with sequencing in many settings.
Publisher: Wiley
Date: 06-2004
Abstract: A major breakthrough in cellular immunology has been the development of HLA class I tetramers to analyze CD8(+) T cell responses. However, in many situations, including persistent virus infection, specific T cell responses are rarely detected using this technology. This raises the question of whether such responses are 'deleted' (or 'exhausted') or present below the conventional detection limit for class I tetramer staining. In particular, persistent hepatitis C virus (HCV) infection is characterized by very weak or apparently absent specific CD8(+) T cell responses, even though they are readily detectable in acute disease. Therefore, we assessed the use of anti-PE-labeled magnetic beads to enrich tetramer-positive HCV-specific T cells and identify previously undetectable populations. Using the enrichment technique, HCV-specific T cells could be detected in the majority of infected in iduals, whereas these responses were not detected using conventional tetramer staining (8/15 vs. 1/15 p=0.01). Magnetic enrichment could reliably detect very rare HCV-specific responses at frequencies of >0.0011% of CD8(+) T cells (approximately 1/million PBMC), and phenotypic analysis of these rare populations was possible. Therefore, this direct ex vivo technique revealed the persistence of very low frequencies of virus-specific CD8(+) T cells during chronic virus infection and is readily transferable to the study of other viral, self- or tumor-specific T cells.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2021
DOI: 10.1007/S15010-021-01599-5
Abstract: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69% at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23 85%), older adults (≥ 70 years: 61, 62, 65 90%), and women (66, 66, 64 90% vs. men 71, 70, 67 93%, each P 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.
Publisher: Frontiers Media SA
Date: 08-08-2019
Publisher: Cold Spring Harbor Laboratory
Date: 10-11-2020
DOI: 10.1101/2020.11.09.374678
Abstract: Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells that utilise a semi-invariant T cell receptor (TCR) α chain and are restricted by the highly conserved antigen presenting molecule MR1. MR1 presents microbial riboflavin biosynthesis derived metabolites produced by bacteria and fungi. Consistent with their ability to sense ligands derived from bacterial sources, MAIT cells have been associated with the immune response to a variety of bacterial infections, such as Mycobacterium spp ., Salmonella spp. and Escherichia coli . To date, MAIT cells have been studied in humans, non-human primates and mice. However, they have only been putatively identified in cattle by PCR based methods no phenotypic or functional analyses have been performed. Here, we identified a MAIT cell population in cattle utilising MR1 tetramers and high-throughput TCR sequencing. Phenotypic analysis of cattle MAIT cells revealed features highly analogous to those of MAIT cells in humans and mice, including expression of an orthologous TRAV1-TRAJ33 TCR α chain, an effector memory phenotype irrespective of tissue localisation, and expression of the transcription factors PLZF and EOMES. We determined the frequency of MAIT cells in peripheral blood and multiple tissues, finding that cattle MAIT cells are enriched in mucosal tissues as well as in the mesenteric lymph node. Cattle MAIT cells were responsive to stimulation by 5-OP-RU and riboflavin biosynthesis competent bacteria in vitro . Furthermore, MAIT cells in milk increased in frequency in cows with mastitis. Following challenge with virulent Mycobacterium bovis , a causative agent of bovine tuberculosis and a zoonosis, peripheral blood MAIT cells expressed higher levels of perforin. Thus MAIT cells are implicated in the immune response to two major bacterial infections in cattle. These data suggest that MAIT cells are functionally highly conserved and that cattle are an excellent large animal model to study the role of MAIT cells in important zoonotic infections.
Publisher: Frontiers Media SA
Date: 04-05-2018
Publisher: American Society for Clinical Investigation
Date: 15-09-2003
DOI: 10.1172/JCI200318509
Publisher: Springer Science and Business Media LLC
Date: 06-05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 23-03-2018
DOI: 10.1101/247205
Abstract: Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo . Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulated and were activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post infection. Activation was modulated via cytokines independently of MR1. MAIT cell-deficient MR1 −/− mice showed enhanced weight loss and mortality to severe (H1N1) influenza. This was ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2 −/− γC −/− mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2018
DOI: 10.1101/490649
Abstract: Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer + cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during resolution and reinfection phases of infection. We observe strong similarities between MAIT cells in humans and mice. Compared with previously published T cell transcriptomes, MAIT cells displayed most similarity to iNKT cells when activated, but to γδ T cells, after resolution of infection. In both species activation leads to strong expression of pro-inflammatory cytokines and chemokines, and also a strong tissue repair signature, recently described in murine commensal-specific H2-M3-restricted T cells. These data define the requirements for, and consequences of, MAIT cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in both species.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0165-2478(02)00224-9
Abstract: Hepatitis C virus (HCV) has infected over 170 million people world wide, and in the majority sets up a chronic infection associated with hepatic inflammation. How it evades host immunity, particularly CD8+ T cells (CTL) is unclear, but two major factors are likely to operate, viral escape mutation and T cell exhaustion. We have investigated the role of CTL in control of infection during acute disease using Class I peptide tetramers. Although the immune response is quite erse and numerous epitopes can be targeted, we observe that, especially during acute disease, one epitope (NS3 1073-81) is commonly recognised in HLA-A2 positive in iduals. However, the levels of response to this epitope (and others) are very much lower if persistence is established. We examined in detail whether the cause of this low level of reactivity is due to mutation within the epitope. We find that, in fact this epitope is highly conserved during chronic infection, at a clonal level, between in iduals, and over time. Thus, although variation within the epitope does occur, lack of reactivity in peripheral blood against this epitope in chronic disease, and loss of control of virus cannot be explained entirely by viral escape. Escape through mutation probably does play an important role in persistence of HCV, but we also discuss other mechanisms which lead to attenuation of T cell responses which may be important in determining the outcome.
Publisher: Cold Spring Harbor Laboratory
Date: 11-05-2021
DOI: 10.1101/2021.05.11.21256877
Abstract: Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1 38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Publisher: Elsevier BV
Date: 09-2004
DOI: 10.1053/J.GASTRO.2004.06.015
Abstract: Cellular immune responses are thought to play a key role in the resolution of primary HCV infection. Although it has been consistently shown that CD4+ T-cell responses are maintained in those with spontaneous resolution but lost in those with persistent infection, the role of CD8+ T-cell responses remains controversial. Previous studies have largely focused on limited HLA alleles and predefined CD8+ T-cell epitopes, and, thus, comprehensive studies remain to be performed. To understand the composition of the immune response associated with spontaneous resolution, we comprehensively mapped CD8+ T-cell responses in 20 HLA- erse persons with resolved HCV infection, using HCV peptides spanning the entire genome. We analyzed the magnitude, breadth, function, and phenotype using ELISpot, class-I tetramers, intracellular cytokine staining, and cytolytic assays. We studied in parallel HCV-specific responses and viral sequence variation in persistent infection. Responses in in iduals with resolved infection were strong and broad with robust proliferation in response to antigen. Responses in those persistently infected were rarely detected ex vivo and, when present, were narrowly directed and weak. However, they also proliferated in vitro. Dominant target epitopes differed among in iduals in both cohorts, despite frequently shared HLA-alleles. These data indicate that persisting, strong CD8+ T-cell responses are observed in the majority of persons with resolved HCV infection and provide support for strategies to boost CD8+ T-cell responses for the prevention or treatment of HCV infection but also highlight the ersity of responses that may need to be elicited to provide protection.
Publisher: Frontiers Media SA
Date: 11-03-2021
DOI: 10.3389/FIMMU.2021.627173
Abstract: Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells that utilize a semi-invariant T cell receptor (TCR) α chain and are restricted by the highly conserved antigen presenting molecule MR1. MR1 presents microbial riboflavin biosynthesis derived metabolites produced by bacteria and fungi. Consistent with their ability to sense ligands derived from bacterial sources, MAIT cells have been associated with the immune response to a variety of bacterial infections, such as Mycobacterium spp., Salmonella spp. and Escherichia coli . To date, MAIT cells have been studied in humans, non-human primates and mice. However, they have only been putatively identified in cattle by PCR based methods no phenotypic or functional analyses have been performed. Here, we identified a MAIT cell population in cattle utilizing MR1 tetramers and high-throughput TCR sequencing. Phenotypic analysis of cattle MAIT cells revealed features highly analogous to those of MAIT cells in humans and mice, including expression of an orthologous TRAV1-TRAJ33 TCR α chain, an effector memory phenotype irrespective of tissue localization, and expression of the transcription factors PLZF and EOMES. We determined the frequency of MAIT cells in peripheral blood and multiple tissues, finding that cattle MAIT cells are enriched in mucosal tissues as well as in the mesenteric lymph node. Cattle MAIT cells were responsive to stimulation by 5-OP-RU and riboflavin biosynthesis competent bacteria in vitro . Furthermore, MAIT cells in milk increased in frequency in cows with mastitis. Following challenge with virulent Mycobacterium bovis , a causative agent of bovine tuberculosis and a zoonosis, peripheral blood MAIT cells expressed higher levels of perforin. Thus, MAIT cells are implicated in the immune response to two major bacterial infections in cattle. These data suggest that MAIT cells are functionally highly conserved and that cattle are an excellent large animal model to study the role of MAIT cells in important zoonotic infections.
Publisher: Wiley
Date: 12-2017
DOI: 10.1038/CTI.2017.53
Publisher: Elsevier BV
Date: 08-2020
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: Wiley
Date: 29-06-2004
Publisher: Wiley
Date: 10-2001
DOI: 10.1046/J.1365-2613.2001.00204.X
Abstract: Viruses have 'studied' immunology over millions of years of coevolution with their hosts. During this ongoing education they have developed countless mechanisms to escape from the host's immune system. To illustrate the most common strategies of viral immune escape we have focused on two murine models of persistent infection, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). LCMV is a fast replicating small RNA virus with a genome prone to mutations. Therefore, LCMV escapes from the immune system mainly by two strategies: 'speed' and 'shape change'. At the opposite extreme, MCMV is a large, complex DNA virus with a more rigid genome and thus the strategies used by LCMV are no option. However, MCMV has the coding capacity for additional genes which interfere specifically with the immune response of the host. These escape strategies have been described as 'camouflage' and 'sabotage'. Using these simple concepts we describe the spectrum of viral escapology, giving credit not only to the researchers who uncovered this fascinating area of immunology but also to the viruses themselves, who still have a few lessons to teach.
Publisher: American Society for Microbiology
Date: 15-06-2005
DOI: 10.1128/JVI.79.12.7852-7859.2005
Abstract: The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8 + T cells. The role of CD4 + CD25 + T regulatory (T reg ) cells in priming and expanding virus-specific CD8 + T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8 + T-cell proliferation and gamma interferon (IFN-γ) frequency were analyzed with/without depletion of T reg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4 + CD25 + T reg cells inhibited anti-CD3/CD28 CD8 + T-cell proliferation and perforin expression. Depletion of CD4 + CD25 + T reg cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion ( P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN-γ-expressing CD8 + T cells. Although stimulated CD8 + T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4 + CD25 + regulatory T cells on CD8 + T-cell proliferation. In conclusion, marked CD4 + CD25 + regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8 + T-cell responses and viral persistence.
Publisher: Microbiology Society
Date: 03-2003
Abstract: A replication-defective herpes simplex virus type 1 (HSV-1) recombinant lacking the glycoprotein H (gH)-encoding gene and expressing a truncated form of the hepatitis C (HCV) E2 glycoprotein (E2-661) was constructed and characterized. We show here that cells infected with the HSV/HCV recombinant virus efficiently express the HCV E2-661 protein. Most importantly, cellular and secreted E2-661 protein were both readily detected by the E2-conformational mAb H53 and despite the high expression levels, only limited amounts of misfolded aggregates were detected in either the cellular or secreted fractions. Furthermore, cell-associated and secreted E2-661 protein bound to the major extracellular loop (MEL) of CD81 in a concentration-dependent manner and both were highly reactive with sera from HCV-infected patients. Finally, BALB/c mice immunized intraperitoneally with the recombinant HSV/HCV virus induced high levels of anti-E2 antibodies. Analysis of the induced immunoglobulin G (IgG) isotypes showed high levels of IgG2a while the levels of the IgG1 isotype were significantly lower, suggesting a Th1-type of response. We conclude that the HSV-1 recombinant virus represents a promising tool for production of non-aggregated, immunologically active forms of the E2-661 protein and might have potential applications in vaccine development.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2009
DOI: 10.1038/NATURE07746
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Publisher: Research Square Platform LLC
Date: 27-07-2021
DOI: 10.21203/RS.3.RS-734011/V1
Abstract: NP 105-113 -B*07:02 specific CD8 + T-cell responses are considered among the most dominant in SARS-CoV-2-infected in iduals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with TCR usage, transcriptome signature, and disease severity (acute N=77, convalescent N=52). We demonstrated a beneficial association of NP 105-113 -B*07:02 specific T-cells in COVID-19 disease progression, linked with expansion of T-cell precursors, high functional avidity and anti-viral effector function. Broad immune memory pools were narrowed post-infection but NP 105-113 -B*07:02 specific T-cells were maintained 6 months after infection with preserved anti-viral efficacy to the SARS-CoV-2 Victoria strain, as well as new Alpha, Beta and Gamma variants. Our data shows that NP 105-113 -B*07:02 specific T-cell responses associate with mild disease and high anti-viral efficacy, pointing to inclusion for future vaccine design.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-01-2011
DOI: 10.1002/HEP.24076
Publisher: American Society for Microbiology
Date: 15-03-2002
DOI: 10.1128/JVI.76.6.2817-2826.2002
Abstract: Both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) lead to chronic infection in a high percentage of persons, and an expanding epidemic of HIV-1-HCV coinfection has recently been identified. These in iduals provide an opportunity for simultaneous assessment of immune responses to two viral infections associated with chronic plasma viremia. In this study we analyzed the breadth and magnitude of the CD8 + - and CD4 + -T-lymphocyte responses in 22 in iduals infected with both HIV-1 and HCV. A CD8 + -T-lymphocyte response against HIV-1 was readily detected in all subjects over a broad range of viral loads. In marked contrast, HCV-specific CD8 + -T-lymphocyte responses were rarely detected, despite viral loads in plasma that were on average 1,000-fold higher. The few HCV-specific responses that were observed were relatively weak and limited in breadth. CD4-proliferative responses against HIV-1 were detected in about half of the coinfected subjects tested, but no proliferative response against any HCV protein was found in these coinfected persons. These data demonstrate a major discordance in immune responses to two persistent RNA viruses. In addition, they show a consistent and profound impairment in cellular immune responses to HCV compared to HIV-1 in HIV-1-HCV-coinfected persons.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2011
Publisher: Springer Science and Business Media LLC
Date: 21-05-2021
Publisher: Springer Science and Business Media LLC
Date: 17-08-2021
DOI: 10.1038/S41467-021-25167-5
Abstract: The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20669
Abstract: Hepatitis C virus (HCV) becomes persistent in the majority of infected in iduals. In doing so, the virus evades host adaptive immune responses, although the mechanisms responsible in this evasion are not clear. Several groups have demonstrated weak or absent HCV-specific CD4+ T cell responses during chronic HCV infection using proliferation assays and, more recently, class II tetramers. However, the functional status of HCV-specific CD4+ T cells in resolved and persistent infection is poorly understood. Using interferon gamma (IFN-gamma) and interleukin 2 (IL-2) enzyme-linked immunospot assays, we analyzed cytokine secretion patterns in chronically infected patients and compared them with those with resolved infection. In the spontaneous resolver group, strong IL-2 secretion in relation to IFN-gamma secretion was observed. However, in the persistently infected group, a consistent and significant loss of IL-2-secreting cells, compared with IFN-gamma-secreting cells, was identified. In vitro addition of IL-2 had a substantial effect in restoring CD4+ T cell activity. In conclusion, failure of IL-2 secretion, as opposed to physical deletion or complete functional unresponsiveness, appears to be an important determinant of the status of CD4+ T cell populations in chronic HCV infection. Loss of IL-2 secretory capacity may lead to disruption of IFN-gamma and proliferative function in vivo-a status that characterizes the cellular immune response in both CD4+ and CD8+ compartments in chronic disease.
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: Springer Science and Business Media LLC
Date: 18-05-2020
DOI: 10.1038/S41416-020-0882-Y
Abstract: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab ( p 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS ( p = 0.008) and Mayo ( p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab ( p = 0.03). CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.
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: Public Library of Science (PLoS)
Date: 26-06-2014
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 04-2016
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2018
DOI: 10.1101/305151
Abstract: Type III interferons (IFN-λ) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-λ4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-λ4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid ersity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-λ4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-λ4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-01-2008
DOI: 10.1002/HEP.22040
Abstract: Hepatitis C virus (HCV) causes chronic infection accompanied by a high risk of liver failure and hepatocellular carcinoma. CD8+ T cell responses are important in the control of viremia. However, the T cell response in chronic infection is weak both in absolute numbers and in the range of epitopes targeted. In order to explore the biology of this response further, we analyzed expression of a panel of natural killer cell markers in HCV compared with other virus-specific T cell populations as defined by major histocompatibility complex class I tetramers. We found that CD161 was significantly expressed on HCV-specific cells (median 16.8%) but not on CD8+ T cells specific for human immunodeficiency virus (3.3%), cytomegalovirus (3.4%), or influenza (3.4%). Expression was seen in acute, chronic, and resolved disease and was greatest on intrahepatic HCV-specific T cells (median 57.6% P < 0.05). Expression of CD161 was also found on hepatitis B virus-specific CD8+ T cells. In general, CD161+CD8+ T cells were found to be CCR7- "effector memory" T cells that could produce proinflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) but contained scanty amounts of cytolytic molecules (granzyme B and perforin) and proliferated poorly in vitro. Expression of CD161 on CD8+ T cells was tightly linked to that of CXCR6, a chemokine with a major role in liver homing. We propose that expression of CD161 indicates a unique pattern of T cell differentiation that might help elucidate the mechanisms of HCV immunity and pathogenesis.
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: Public Library of Science (PLoS)
Date: 15-12-2016
Publisher: American Society for Microbiology
Date: 23-02-2017
Abstract: Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, EcEs062_16 and EcEs089_16, isolated from the sera of febrile patients in Esmeraldas City, in the northern coastal province of Esmeraldas, Ecuador, in April 2016. These are the first complete ZIKV genomes to be reported from Ecuador.
Publisher: Wiley
Date: 13-11-2002
DOI: 10.1002/1521-4141(200212)32:12<3366::AID-IMMU3366>3.0.CO;2-#
Publisher: American Society of Hematology
Date: 02-2005
DOI: 10.1182/BLOOD-2004-06-2336
Abstract: CD8+ T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4+ T-helper cells. To determine the relationship between HIV-1–induced CD4+ T-cell depletion and hepatitis C virus (HCV)–specific CD8+ T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8+ T-cell responses to the entire HCV polyprotein were determined by using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1–associated CD4+ depletion was associated with significantly lower HCV-specific CD8+ T cells (R = 0.48, P & .0001). In contrast, declining CD4+ counts over the same range were not associated with diminished Epstein-Barr virus (EBV)– (R = 0.19, P = .31) or HIV-1–specific (R = –0.13, P = .60) CD8+ T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8+ T-cell responses are sensitive to absolute CD4+ T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.
Publisher: Springer Science and Business Media LLC
Date: 05-2023
DOI: 10.1038/S41591-023-02343-2
Abstract: Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated in iduals with severe obesity (BMI 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 in iduals with severe obesity compared to 41 control in iduals with normal BMI (BMI 18.5–24.9 kg/m 2 ). We found that 55% of in iduals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of in iduals with normal BMI ( P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for in iduals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of in iduals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in in iduals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.
Publisher: eLife Sciences Publications, Ltd
Date: 24-12-2021
DOI: 10.7554/ELIFE.50324
Abstract: Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected in iduals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIV BAL potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites.
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 02-06-2018
DOI: 10.1111/IMCB.12056
Publisher: American Society for Microbiology
Date: 15-06-2002
DOI: 10.1128/JVI.76.12.6104-6113.2002
Abstract: The hepatitis C virus (HCV)-specific CD8 + -T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8 + -T-cell responses in the context of erse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive in iduals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8 + -T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an in idual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8 + -T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S1286-4579(01)01510-6
Abstract: Hepatitis C virus (HCV) readily causes a persistent infection, although some in iduals spontaneously control infection. 'Successful' immune responses appear to be multi-specific and sustained-including a major role for CD4(+)T cells. Some antiviral CD8(+)T cells show reduced capacity to secrete antiviral cytokines either temporarily ('stunning') or in the long term ('stunting'). The co-ordination of multiple immune effector functions may be required to gain control of HCV.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2002
Abstract: Hepatitis C virus (HCV) readily sets up a persistent infection and is a major cause of liver disease worldwide. Interferon alfa and ribavirin therapy lead to sustained clearance of virus in 31% to 64% of patients with type 1 and non-type 1 genotypes, respectively. It is not clear to what extent these drugs act directly to reduce HCV replication, or indirectly via host immune responses, and what evoked immune responses are associated with clinical outcome. We have examined prospectively 15 patients with chronic HCV infection before, during, and after combination therapy. Quantitative assays for HCV antigen-specific CD4+ and CD8+ T-cell responses, and flow cytometric assays for analysis of the phenotype of T cells, in addition to viral sequencing of core protein, were performed throughout the treatment and follow-up period over 18 months. We found enhancement of proliferative T-cell responses during therapy. Proliferative responses are strikingly heterogeneous in terms of specificity, kinetics, and magnitude. Proliferative responses are often not associated with interferon-gamma release. T-cell responses are rarely sustained irrespective of treatment outcome and this is not due to the evolution of new immune escape variants. T-cell responses tend to peak late in the course of treatment. In conclusion, combination therapy for HCV has a transient effect on host virus-specific T cells in the blood. Induction of sustained T-cell responses may require additional immune modulation later in therapy.
Publisher: Public Library of Science (PLoS)
Date: 10-06-2013
Publisher: Oxford University Press (OUP)
Date: 16-03-2020
Abstract: Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.
Publisher: Oxford University Press (OUP)
Date: 07-2010
Publisher: Elsevier BV
Date: 2021
Publisher: American Society for Clinical Investigation
Date: 20-01-2005
DOI: 10.1172/JCI200523084
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: American Society for Microbiology
Date: 05-2011
DOI: 10.1128/JVI.00374-11
Publisher: Wiley
Date: 04-2005
DOI: 10.1111/J.1440-1711.2005.01321.X
Abstract: CMV-specific memory CD8(+) T cells accumulate over time to reach high frequencies amongst peripheral blood lymphocytes - a phenomenon termed 'memory inflation'. Using tetramer staining on s les from a large number of subjects and multivariate regression analysis, we were able to relate this to the phenotype of CD8(+) T cells. We made the following observations: (i) CD85j (ILT-2/LIR-1) was highly expressed alongside CD57 - an established effector memory marker - on CMV-specific CD8(+) T cells (ii) on CD8(+) T cells as a whole, with increasing age, CD57 and CD85j (ILT-2/LIR-1) expression increased whereas CCR7 expression decreased, indicating increasing maturation of the total CD8(+) T-cell compartment with age (iii) unit increases in the percentage of CMV-specific CD8(+) T cells expressing CD57 and CD85j (ILT-2/LIR-1) were associated with incremental expansion of these T-cell populations (iv) CMV seropositivity is associated with a marked effect on the overall phenotype of CD8(+) T cells (at any given age, CMV seropositivity is associated with an 18.7% increase in CD85j (ILT-2/LIR-1) expression) and (v) from our observations we estimated from this an apparent 'ageing effect' of CMV on CD8(+) T cells of 35.4 years. The data presented are consistent with a predictable, unidirectional and linear model of virus specific T-cell differentiation and maturation.
Location: India
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for paul klenerman.