ORCID Profile
0000-0002-4644-1982
Current Organisations
University of Patras
,
Aristotle University of Thessaloniki
,
University of Western Australia
,
Cluster of Bioeconomy and Environment of Western Macedonia, University of Western Macedonia
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Publications
Pulmonary Mycobacterium celatum immune restoration disease: Immunopathology and response to corticosteroid therapy [4]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-11-2005
Resumption of HIV replication is associated with monocyte/macrophage derived cytokine and chemokine changes: results from a large international clinical trial
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
Immune Reconstitution Disorders in Patients With HIV Infection: From Pathogenesis to Prevention and Treatment
Publisher: Springer Science and Business Media LLC
Date: 21-06-2014
DOI: 10.1007/S11904-014-0213-0
Abstract: An immune reconstitution disorder occurs in up to 40 % of severely immunodeficient HIV patients who commence antiretroviral therapy (ART), with an immune reconstitution inflammatory syndrome (IRIS) being encountered most commonly. Differences in the immunopathogenesis of an IRIS associated with different types of pathogen have become apparent but common features have also been defined. These include severe immunodeficiency prior to commencing ART associated with a high pathogen load and 'compensatory' immune responses, particularly innate immune responses, which inadequately control the pathogen and increase the risk of immunopathology as the immune system recovers on ART. Prevention of an IRIS may be achieved by optimising therapy for opportunistic infections before ART is commenced, delaying ART or using immunomodulatory therapy to prevent or suppress the immune response that causes the immunopathology. However, further clinical studies are required to examine these options in a systematic manner for the various types of IRIS.
Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings
Publisher: Elsevier BV
Date: 08-2008
Could natural killer cells compensate for impaired CD4+ T-cell responses to CMV in HIV patients responding to antiretroviral therapy?
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.CLIM.2009.03.518
Abstract: We evaluated NK cell subsets and functions in previously immunodeficient HIV patients responding to ART. Cytokine receptor mRNA was quantitated in purified CD56+ cells. Data were correlated with CD4+ T-cell counts and IFNgamma responses to CMV. NK cell IFNgamma responses to K562 cells and proportions of CD56lo NK cells were correlated in patients (p < 0.001) and both were lower than in controls (p < 0.001 and p = 0.008, respectively), so all patients had poor NK cell function. Proportions of CD56hi NK cells correlated inversely with current CD4+ T-cell counts (p = 0.006) and perforin expression in CD56hi NK cells was higher in patients than controls (p < 0.05). Hence increased proportions and cytolytic function of CD56hi NK cells may partially compensate for CD4+ T-cell deficiency. NK cell IFNgamma responses correlated inversely with expression of IL-10 and IL-12 receptor mRNA. Expression of these transcripts is reduced by exposure to the cytokines, which may reflect immune activation in immunodeficient patients.
The number and function of circulating dendritic cells may limit effector memory CD4+ T-cell responses in HIV patients responding to antiretroviral therapy
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.CLIM.2008.03.517
Abstract: Some HIV patients who previously experienced severe immunodeficiency retain low pathogen-specific T-cell responses despite a virological response to antiretroviral therapy (ART). To identify correlates with dysfunction in accessory cell populations, HIV patients were stratified into groups maintaining high or low CD4(+) T-cell IFN-gamma responses to cytomegalovirus (CMV) over 4-8 years on ART. Myeloid dendritic cells (mDC), plasmacytoid (p) DC, M-DC8(+) cells and monocytes were enumerated and mRNA of cytokines and activation molecules were quantitated in purified subpopulations. Proportions of pDC were lower (p=0.043) and mDC were higher (p=0.043) in low responders. TRAIL receptor 2 (DR5) mRNA levels in pDC (p=0.0008) and mDC (p=0.0062) were lower in high responders compared to controls. Levels of IL-15 mRNA were higher in mDC from high responders (p=0.015) and levels of IL-10 mRNA were higher in M-DC8(+) cells from low responders (p=0.036). Hence CMV-specific CD4(+) T-cell IFN-gamma responses may be affected by numbers and function of circulating DC.
Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome
Publisher: Frontiers Media SA
Date: 15-08-2109
Immune restoration diseases reflect diverse immunopathological mechanisms
Publisher: American Society for Microbiology
Date: 10-2009
DOI: 10.1128/CMR.00015-09
Abstract: Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For ex le, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal s le sets and clinical presentations are required to illuminate the erse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.
Immunopathogenesis of HIV Coinfections
Publisher: Springer New York
Date: 2014
Association of Increased Hepatitis C Virus (HCV)-Specific IgG and Soluble CD26 Dipeptidyl Peptidase IV Enzyme Activity with Hepatotoxicity after Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus-HCV-Coinfected Patients
Publisher: Oxford University Press (OUP)
Date: 15-11-2002
DOI: 10.1086/344892
Abstract: Hepatotoxicity was investigated, using plasma collected before and during treatment, in 16 human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients who responded to highly active antiretroviral therapy (HAART), during a retrospective longitudinal study. Eleven patients experienced hepatotoxicity (i.e., a >3-fold increase in alanine aminotransferase level) while receiving HAART, including 4 patients with clinical hepatitis. Control subjects were 5 patients without hepatotoxicity. Markers of HCV-specific immune responses (HCV core-specific immunoglobulin G [IgG] antibody), T cell activation (soluble [s] CD26 dipeptidyl peptidase IV [DPP IV] enzyme activity), and inflammation (nitrate/nitrite and soluble tumor necrosis factor receptor I [sTNFRI] levels) were correlated with liver damage and immune reconstitution. All patients with hepatotoxicity had increased HCV core-specific IgG antibody and sCD26 (DPP IV) activity but did not have increased nitrate/nitrite or sTNFRI levels. Hepatotoxicity without clinical hepatitis was associated with increased CD8 T cell counts. Thus, hepatotoxicity in HIV-HCV-coinfected patients who respond to HAART is associated with increased HCV-specific immune responses and T cell activation.
Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patientswith cryptococcal meningitis and cryptococcosis- Associated immune reconstitution inflammatory syndrome
Publisher: Oxford University Press (OUP)
Date: 08-2013
Mediators of Innate and Adaptive Immune Responses Differentially Affect Immune Restoration Disease Associated withMycobacterium tuberculosisin HIV Patients Beginning Antiretroviral Therapy
Publisher: Oxford University Press (OUP)
Date: 12-2010
DOI: 10.1086/657082
Abstract: Initiation of antiretroviral therapy (ART) in human immunodeficiency virus patients with treated or unrecognized Mycobacterium tuberculosis infection may result in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB), respectively. Both conditions appear to be immune restoration disease but their immunopathogenesis is not completely understood. Chemokines and cytokines produced by the innate immune system (CCL2, CXCL8, CXCL9, CXCL10, and interleukin 18 [IL-18]) were assayed in plasma from unstimulated whole blood cultures obtained from 15 TB-IRIS case patients, 11 ART-TB case patients, and matched control participants over 24 weeks of ART. When compared with control participants, levels of IL-18 and CXCL10 were higher in TB-IRIS case patients (P = .002 and .006, respectively), whereas CCL2 was lower (P = .006). IL-18 level was higher in ART-TB case patients (P = .002), but CXCL10 was only marginally higher (P = .06). When TB-IRIS case patients were compared with ART-TB case patients, IL-18 was higher in ART-TB (P = .03), whereas CXCL10 was higher in TB-IRIS (P = .001). Using receiver operating characteristic curves, pre-ART levels of CCL2, CXCL10, and IL-18 were predictive of TB-IRIS and additive to IFN-γ responses. Perturbations of the innate immune response to M. tuberculosis before and during ART may contribute to the immunopathology of TB-IRIS, whereas elevated IL-18 alone suggests adaptive immune responses predominate in ART-TB. These findings may have implications for therapy in TB-IRIS.
Epstein–Barr virus infection, B-cell dysfunction and other risk factors converge in gut-associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1418
Abstract: Multiple sclerosis is associated with Epstein–Barr virus (EBV) infection, B‐cell dysfunction, gut dysbiosis, and environmental and genetic risk factors, including female sex. A disease model incorporating all these factors remains elusive. Here, we hypothesise that EBV‐infected memory B cells (MBCs) migrate to gut‐associated lymphoid tissue (GALT) through EBV‐induced expression of LPAM‐1, where they are subsequently activated by gut microbes and/or their products resulting in EBV reactivation and compartmentalised anti‐EBV immune responses. These responses involve marginal zone (MZ) B cells that activate CD4 + T‐cell responses, via HLA‐DRB1, which promote downstream B‐cell differentiation towards CD11c + /T‐bet + MBCs, as well as conventional MBCs. Intrinsic expression of low‐affinity B‐cell receptors (BCRs) by MZ B cells and CD11c + /T‐bet + MBCs promotes polyreactive BCR/antibody responses against EBV proteins (e.g. EBNA‐1) that cross‐react with central nervous system (CNS) autoantigens (e.g. GlialCAM). EBV protein/autoantigen‐specific CD11c + /T‐bet + MBCs migrate to the meningeal immune system and CNS, facilitated by their expression of CXCR3, and induce cytotoxic CD8 + T‐cell responses against CNS autoantigens lified by BAFF, released from EBV‐infected MBCs. An increased abundance of circulating IgA + MBCs, observed in MS patients, might also reflect GALT‐derived immune responses, including disease‐enhancing IgA antibody responses against EBV and gut microbiota‐specific regulatory IgA + plasma cells. Female sex increases MZ B‐cell and CD11c + /T‐bet + MBC activity while environmental risk factors affect gut dysbiosis. Thus, EBV infection, B‐cell dysfunction and other risk factors converge in GALT to generate aberrant B‐cell responses that drive pathogenic T‐cell responses in the CNS.
Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors
Publisher: American Society of Hematology
Date: 18-01-2022
DOI: 10.1182/BLOODADVANCES.2021006211
Abstract: The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each in idual disease context.
A prospective large-scale study of methods for the detection of latent Mycobacterium tuberculosis infection in refugee children
Publisher: BMJ
Date: 30-04-2010
Abstract: BACKGROUND Diagnosis of latent tuberculosis infection (LTBI) is a cornerstone of the health assessment of resettled high incidence populations, particularly in children. Two blood-based interferon gamma release assays (IGRAs), T-SPOT.TB and QFT-Gold in-tube (QFT-GIT), have greater sensitivity and specificity than the tuberculin skin test (TST), but their performance as screening tools for LTBI in children, especially refugee children, remains unclear. METHODS 524 African and ethnic Burmese children, including 107 under 3 years of age, were prospectively enrolled in a comparison of the T-SPOT.TB and QFT-GIT. The TST was also performed in 342 of the children. RESULTS The T-SPOT.TB and QFT-GIT had similar rates of positivity (8% and 10%, respectively) and showed good concordance when both tests gave definitive results (kappa=0.78 p<0.0001). However, the IGRAs had significant failure rates: 15% of QFT-GIT gave indeterminate results due to failed mitogen response and 14% of T-SPOT.TB results were inconclusive, largely because of insufficient mononuclear leucocyte yields. Failure of the QFT-GIT mitogen response was associated with African ethnicity and co-morbid infections, particularly with helminths. The TST results showed poor concordance ( approximately 50%) with both IGRAs. CONCLUSIONS It is reasonable to screen using either IGRA with follow-up by the alternative if the test fails. In general, the QFT-GIT is the preferred option for non-African populations but the T-SPOT.TB is recommended when there are epidemiological and/or clinical high risk factors for TB infection. However, both IGRAs have methodological and performance characteristics that limit their usefulness in refugee children, highlighting the need for continued development of screening strategies.
Interferon-γ Response by Peripheral Blood Mononuclear Cells to Hepatitis C Virus Core Antigen Is Reduced in Patients with Liver Fibrosis
Publisher: Oxford University Press (OUP)
Date: 15-11-2003
DOI: 10.1086/379252
Abstract: Liver fibrosis was correlated with immunological parameters. Peripheral blood mononuclear cells (PBMCs) from patients with low fibrosis scores had more [corrected] interferon (IFN)-gamma-producing cells than did patients with higher fibrosis scores, when stimulated with hepatitis C virus (HCV) core antigen. Irrespective of liver fibrosis score, cells from all cytomegalovirus (CMV)-seropositive patients had similar IFN-gamma responses, when stimulated by CMV antigen, so patients with fibrosis did not have a broad-spectrum immunodeficiency. IFN-gamma response by PBMCs to HCV core antigen may provide a useful marker of the severity of liver disease in patients with hepatitis C.
Persistent HIV-1 replication does not explain low levels of T-cell interferon-γ mRNA and elevated serum NO2–/NO3– in patients with stable CD4 T-cell responses to HAART
Publisher: Oxford University Press (OUP)
Date: 31-08-2004
DOI: 10.1111/J.1365-2249.2004.02589.X
Abstract: HIV-1 infected patients adherent to HAART and displaying stable increases in CD4 T-cell counts differ in their control of HIV replication and one might expect this to reflect depressed immune function. The importance of virological control in functional immune reconstitution was investigated in HIV-1 infected patients who maintained high or undetectable plasma HIV RNA levels over 2–4 years on HAART (discordant and complete responders, respectively). Immunocompetance and immune activation were assessed directly ex vivo and after a short period of culture, as HIV replication in cultures from viraemic patients may artificially depress responses. Expression of cytokine (interferon-γ, interleukin-5) and chemokine receptor (CCR5, CRTH2) mRNA were determined and soluble CD30 and NO2–/NO3– were measured in sera. Unstimulated cells from all patients had low levels of IFNγ mRNA relative to uninfected controls. Discordant responders had more IFNγ, IL-5 and CCR5 mRNA in mitogen-stimulated PBMC than complete responders, where the difference could be attributed to CD8-T-cells. Serum NO2–/NO3– levels were significantly higher in all patients than controls, with no difference between complete and discordant responders. Serum CD30 levels were significantly higher in discordant responders. These data indicate a persistent immune deficit in immune reconstituted patients irrespective of HIV viral load and associate persistent viral replication with lymphocyte activation, probably involving CD8 T-cells.
MHC Haplotypes Affect the Expression of Opportunistic Infections in HIV Patients
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1016/S0198-8859(00)00239-1
Abstract: This study explores whether MHC genes affect manifestations of opportunistic infections in HIV patients not treated with highly active antiretroviral therapy (HAART) and immunopathologic responses to pre-existing infections in patients who achieved immune reconstitution following HAART (i.e., "immune restoration diseases" or IRD). HLA-B27 and B17 were relatively rare in all HIV patients, but no HLA-B alleles significantly affected cytomegalovirus (CMV) or Mycobacterium avium complex (MAC) disease in patients who had not received HAART. However coexpression of alleles previously defined as the 44.1 ancestral haplotype (HLA-A2, -B44, and -DR4) was more common in the MAC and CMV patients. After HAART, HLA-B44 and (HLA-A2, -B44, -DR4) were found in 66% and 33%, respectively, of patients who experienced an IRD manifested as CMV retinitis and/or encephalomyelitis. This was confirmed by examination of microsatellite alleles, where the C1_2_5 locus in the class I region was most concordant with the 44.1 haplotype in the patients. HLA-B44 was not associated with IRD initiated by Mycobacterium sp, cutaneous VZV or HSV, or HCV infections, suggesting distinct pathologic mechanisms are responsible. CMV retinitis/encephalomyelitis IRD patients had marginally lower pretreatment CD4 T-cell counts, but indices of immune reconstitution were similar in all groups and independent of HLA-B44.
Endothelial function in HIV-infected patients receiving protease inhibitor therapy: Does immune competence affect cardiovascular risk?
Publisher: Oxford University Press (OUP)
Date: 11-2003
DOI: 10.1093/QJMED/HCG145
Abstract: The use of HIV protease inhibitors (PIs) as a component of combination antiretroviral therapy in HIV-infected patients has been associated with dyslipidaemia, but its significance as a risk factor for cardiovascular disease is unclear. Endothelial dysfunction is an early phase of atherogenesis that may be assessed non-invasively with ultrasonography in vivo. To evaluate vascular function and investigate potential determinants of endothelial dysfunction of the peripheral circulation in PI-treated, HIV-infected men with dyslipidaemia. Observational, case-control study. We studied 24 HIV-infected, PI-treated men with dyslipidaemia and 24 normolipidaemic, healthy male controls matched for age and body mass index. Brachial artery endothelial function was studied using high-resolution ultrasound and computerized edge-detection software. This non-invasive technique measured post-ischaemic flow-mediated dilatation (FMD), and the endothelium-independent vasodilatory response to glyceryl trinitrate (GTN). Within the HIV patient group, FMD was significantly associated with percentage of 'naïve' CD4 + 45RA + T cells (p = 0.03), while plasma lipid/lipoprotein and insulin levels, body mass, and smoking status did not correlate with endothelial function. FMD was not significantly different between the study group and the controls. The atherogenic potential of PI-associated dyslipidaemia may be attenuated in HIV-infected patients with decreased immune competence, reflecting a possible contribution of cell-mediated immune responses to the pathogenesis of atherosclerosis.
Isotype Diversification of IgG Antibodies to HIV Gag Proteins as a Therapeutic Vaccination Strategy for HIV Infection
Publisher: MDPI AG
Date: 09-08-2013
Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.CLIM.2006.04.570
Abstract: The adverse effects of immune activation on CD4(+) T-cell recovery and the relationship between CD4(+) T-cell counts and effector T-cell function were examined in HIV-1 patients receiving long-term effective ART. Patients with nadir CD4(+) T-cell counts 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified by current CD4(+) T-cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. We assessed proliferation (Ki67), activation (HLA-DR, CD38) and replicative senescence (CD57) by flow cytometry and CD4(+) T-cell responses to CMV by IFN-gamma ELISpot. Proportions of CD4(+) T-cells expressing HLA-DR or CD57 were strong univariate predictors of total (P = 0.0002 and P = 0.002) and naive (P < 0.0001 and P < 0.0001, respectively) CD4(+) T-cell counts, suggesting that CD4(+) T-cell activation drives the depletion of naive CD4(+) T-cells. This was clearest in patients with a small/undetectable thymus. IFN-gamma responses to CMV were similar in patients with low or high CD4(+) T-cell counts.
Disorders of Immune Reconstitution in Patients with HIV Infection Responding to Antiretroviral Therapy
Publisher: Springer Science and Business Media LLC
Date: 02-2007
DOI: 10.1007/S11904-007-0003-Z
Abstract: Patients with HIV infection who were very immunodeficient before achieving a virologic response to antiretroviral therapy (ART) may experience various disorders of immune reconstitution. Immune restoration disease occurs in approximately 10% to 50% of patients and results from the restoration of a pathogen-specific immune response that causes immunopathology and presents as tissue inflammation or cellular proliferative disease. Opportunistic infections occur in no more than 5% of patients, but approximately one half of these patients have higher than expected CD4 T-cell counts and appear to have residual immune dysfunction. Autoimmune disease may arise because the reconstituted immune system confers an increased susceptibility to immune dysregulation but there may be different mechanisms because Graves' disease presents after a median time of about 2 years of ART whereas systemic lupus erythematosus presents earlier. Persistent CD4 T-cell deficiency (< 500/microL) affects up to 60% of patients and appears to reflect depletion of the naïve T-cell pool that results from low production and/or increased turnover of cells.
Alleles of the gene encoding IL-1[alpha] may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2004
DOI: 10.1097/01.AIDS.0000131352.06784.C6
Abstract: Some HIV patients treated with highly active antiretroviral therapy (HAART) do not resolve their plasma viraemia or HIV RNA can reappear after a period of virological control. We investigate whether polymorphisms in cytokine genes affect the control of plasma HIV RNA over 5 years on HAART. The study utilized adult HIV-infected patients in Western Australia. Plasma HIV-RNA levels were assessed from commencement of HAART in patients who had a CD4 T-cell count less than 100 cells/microl before HAART and achieved immune reconstitution assessed by CD4 T-cell counts. Control of plasma viraemia could be predicted from carriage of allele 2 at position -889 in the IL1A gene (IL1A-889*2). This was significant when assessed by the proportion of patients with a plasma HIV-RNA level of 400 copies/ml or less (P = 0.002). At 48 months post-HAART, proportions were approximately 0.76, 0.51 and 0.32 for IL1A (1,1), (1,2) and (2,2) patients, respectively. The outcome was independent of the patients' CD4 T-cell counts before or on therapy, drug regimen or age. Polymorphisms in IL6, TNFA, IL1B or IL12B had less significant effects, which became marginal when IL1A was included in the statistical model. IL1A-889 was in linkage disequilibrium with a non-synonymous polymorphism at IL1A+4845. Alleles carried at IL1A-889 or IL1A+4845 may predict the control of HIV replication in previously immunodeficient patients responding to HAART.
Tuberculosis (TB)-associated immune reconstitution inflammatory syndrome in TB-HIV co-infected patients in Malaysia: prevalence, risk factors, and treatment outcomes
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/SH14093
Abstract: Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication of antiretroviral therapy (ART) in countries with high rates of endemic TB, but data from South-East Asia are incomplete. Identification of prevalence, risk factors and treatment outcomes of TB-IRIS in Malaysia was sought. Methods: A 3-year retrospective study was conducted among TB-HIV co-infected patients treated at the University of Malaya Medical Centre. Simple and adjusted logistic regressions were used to identify the predictors for TB-IRIS while Cox regression was used to assess the influence of TB-IRIS on long-term CD4 T-cell recovery. Results: One hundred and fifty-three TB-HIV patients were enrolled, of whom 106 had received both anti-TB treatment (ATT) and ART. The median (IQR) baseline CD4 T-cell count was 52 cells μL–1 (13–130 cells μL–1). Nine of 96 patients (9.4%) developed paradoxical TB-IRIS and eight developed unmasking TB-IRIS, at a median (IQR) time of 27 (12–64) and 19 (14–65) days, respectively. In adjusted logistic regression analysis, only disseminated TB was predictive of TB-IRIS [OR: 10.7 (95% CI: 1.2–94.3), P = 0.032]. Mortality rates were similar for TB-IRIS (n = 1, 5.9%) and non-TB-IRIS (n = 5, 5.7%) patients and CD4 T-cell recovery post-ART was not different between the two groups (P = 0.363). Conclusion: Disseminated TB was a strong independent predictor of TB-IRIS in Malaysian HIV-TB patients after commencing ART. This finding underscores the role of a high pathogen load in the pathogenesis of TB-IRIS so interventions that reduce pathogen load before ART may benefit HIV patients with disseminated TB.
Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy
Publisher: Mary Ann Liebert Inc
Date: 02-2006
Abstract: The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was ided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.
Association of HIV-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57:01 Is Only Observed in Viremic Controllers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-08-2007
HIV patients on antiretroviral therapy have high frequencies of CD8 T cells specific for Immediate Early protein-1 of cytomegalovirus
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2005
DOI: 10.1097/01.AIDS.0000163931.68907.7E
Abstract: To assess the frequency and phenotype of cytomegalovirus (CMV)-specific CD8 T cells in previously immunocompromised HIV patients with stable undetectable HIV viremia due to highly active antiretroviral therapy (HAART). Twenty-one CMV-seropositive HIV patients with nadir CD4 T-cell counts < 50 x 10(6) cells/l, at least 4 years on HAART and 6 months of complete viral suppression (< 50 HIV RNA copies/ml) and 12 CMV-seropositive, HIV-seronegative age/sex-matched controls were studied. CD4 and CD8 T-cell responses to whole CMV and two HLA-A*02 restricted CMV peptides [NLV from pp65 and VLE from Immediate Early 1 (IE1)] were measured by interferon (IFN)gamma ELISpot. Phenotypes of peptide-specific CD8 T cells were determined by tetramer staining. In the ELISpot assay, HIV patients had significantly more CD8 T cells producing IFN gamma in response to VLE than controls, whereas numbers of NLV-specific and CMV-specific IFN gamma spots were similar. Four HIV patients and one control had large VLE and/or NLV-specific CD8 T-cell populations despite the absence of CMV-specific CD4 T cells. The majority of peptide-specific CD8 T cells from HIV patients and controls were CD28-, CD45RO+ and CD45RA-. However, a significantly higher proportion of VLE-specific CD8 T cells expressed perforin compared to NLV-specific CD8 T cells in HIV patients. HIV patients had elevated numbers of IE1-specific, IFNgamma-producing perforin-positive CD8 T cells compared to controls. As IE1 is expressed early during CMV reactivation, these cells may be important for preventing CMV replication to pathogenic levels. In addition, CMV-specific CD4 T cells are not essential for maintenance of large populations of CMV-specific CD8 T cells in aviremic HIV patients on HAART.
Combined analysis of two-year follow-up from two open-label randomized trials comparing efficacy of three nucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1 infection: Ozcombo 1 and 2
Publisher: Informa UK Limited
Date: 08-2003
CD31 (PECAM-1) is a marker of recent thymic emigrants among CD4+ T-cells, but not CD8+ T-cells or gammadelta T-cells, in HIV patients responding to ART
Publisher: Wiley
Date: 12-01-2010
DOI: 10.1038/ICB.2009.108
Abstract: Some severely immunodeficient HIV patients experience poor recovery of CD4(+) T-cell counts on antiretroviral therapy (ART). Evaluation of the function of thymopoiesis in T-cell production in in idual patients requires a simple marker of T-cells that have recently emigrated from the thymus. Here, we address whether expression of CD31 on CD4(+) T-cells, CD8(+) T-cells, regulatory T-cells and gammadelta T-cells correlates with other indicators of thymus function. Adult HIV-1 patients (n=27) with nadir CD4(+) T-cell counts <100 per mul and a sustained virological response to ART and healthy controls (n=23) were studied. CD31 expression was assessed by flow cytometry, T-cell receptor excision circles content by real-time PCR and thymic volume by spiral computed tomography. Proportions of CD4(+) T-cells expressing CD45RA and CD31 declined with age in HIV patients (P=0.03) and healthy controls (P<0.0001), and correlated directly with other markers of thymus function. In controls, proportions of CD8(+) T-cells expressing CD45RA and CD31 declined with age (P=0.003) and correlated directly with some markers of thymus function, but this was not seen in HIV patients. Proportions of CD45RA(+) CD31(+) gammadelta T-cells were higher in patients than controls (P=0.007) and did not correlate with thymus volume. In controls, proportion of gammadelta T-cells co-expressing CD45RA and CD31 increased with age (P=0.002). These data support the use of CD31 as a marker of recent thymic origin in CD4(+) T-cells, but not CD8(+) T-cells in HIV patients receiving ART. In such patients, CD31 expression is unlikely to indicate thymic origin in gammadelta T-cells.
'Tuberculosis' after commencing antiretroviral therapy in HIV patients from countries where Mycobacterium tuberculosis infection is common
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-02-2006
Antibody-mediated control of HIV-1 infection through an alternative pathway
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2019
The Next Generation of Diagnostic Tests for Primary Immunodeficiency Disorders
Publisher: Oxford University Press (OUP)
Date: 02-07-2020
Tuberculosis After Commencing Antiretroviral Therapy for HIV Infection Is Associated With Elevated CXCL9 and CXCL10 Responses to Mycobacterium tuberculosis Antigens
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2012
Thymic tissue is not evident on high-resolution computed tomography and [(1)(8)F]fluoro-deoxy-glucose positron emission tomography scans of aviraemic HIV patients with poor recovery of CD4(+) T cells
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2011
Immune reconstitution syndrome is not a single entity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-04-2008
Susceptibility to opportunistic infections in HIV-infected patients with increased CD4 T-cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells
Publisher: Wiley
Date: 04-2007
DOI: 10.1111/J.1468-1293.2007.00445.X
Abstract: HIV-infected patients responding to combination antiretroviral therapy (ART) after experiencing severe immunodeficiency may exhibit persistent immune defects and occasionally experience opportunistic infections (OIs) despite increased CD4 T-cell counts. The investigation of immune defects in such patients was examined in this study. CD4 effector memory T-cell (T(em)-cell) function [assessed by blood cytomegalovirus (CMV) interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) counts] and B-cell dysregulation [assessed by serum immunoglobulin A (IgA) and IgE levels] were examined in 27 patients with increased CD4 T-cell counts after receiving ART for over 2 years. Two of these patients and one other had developed OIs on ART and are described in detail. Serum levels of IgA and IgE were higher than reference intervals (P<0.001) and CMV IFN-gamma ELISPOT counts were lower than those in non-HIV-infected controls (P<0.001) in the HIV-infected patients. Low CMV IFN-gamma ELISPOT counts were associated with high IgA levels (r=-0.5, P=0.01, Spearman's correlation test) and segregated with high IgE levels (P=0.06, Fisher's test). CMV IFN-gamma ELISPOT counts and serum IgA and IgE levels did not change significantly over a median time of 35 (range 8-60) months after the first measurement, whereas CD4 T-cell counts increased. All three patients who experienced OIs had repeatedly low CMV IFN-gamma ELISPOT counts and increased serum levels of IgA and/or IgE. Low CD4 T(em)-cell function and B-cell dysregulation are immune defects that may persist independently of changes in the CD4 T-cell count in HIV-1-infected patients responding to ART and are associated with an increased risk of developing an OI.
Antiviral functions of human immunodeficiency virus type 1 (HIV-1)-specific IgG antibodies
Publisher: Frontiers Media SA
Date: 04-07-2017
Persistent immune activation in chronic HIV infection: Do any interventions work?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2013
Functional STAT3 deficiency compromises the generation of human T follicular helper cells
Publisher: American Society of Hematology
Date: 26-04-2012
DOI: 10.1182/BLOOD-2011-11-392985
Abstract: T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4+ T cells to the Tfh lineage, because IL-12 induces naive human CD4+ T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4+ T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12–induced expression of IL-21 by human CD4+ T cells. Defective expression of IL-21 by STAT3-deficient CD4+ T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4+CXCR5+ T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
Imbalanced effector and regulatory cytokine responses may underlie mycobacterial immune restoration disease
Publisher: Springer Science and Business Media LLC
Date: 29-04-2008
Abstract: Immune restoration disease (IRD) is an adverse consequence of antiretroviral therapy, where the restored pathogen-specific response causes immunopathology. Mycobacteria are the pathogens that most frequently provoke IRD and mycobacterial IRD is a common cause of morbidity in HIV-infected patients co-infected with mycobacteria. We hypothesised that the excessive effector immune response in mycobacterial IRD reflects impaired regulation by IL-10. We studied two patients who experienced mycobacterial IRD during ART. One patient developed a second episode of IRD with distinct clinical characteristics. Findings were compared with patients 'at risk' of developing IRD who had uneventful immune recovery. Peripheral blood mononuclear cells (PBMC) from all subjects were stimulated with mycobacterial antigens in the form of purified protein derivative (PPD). Supernatants were assayed for IFNγ and IL-10. In response to PPD, PBMC from IRD patients generated IFNγ during the first IRD episode, whilst cells from non-IRD controls produced more IL-10. We present preliminary data from two HIV-infected patients showing an imbalance between IFNγ and IL-10 responses to mycobacterial antigens during mycobacterial IRD. Our findings suggest that imbalanced effector and regulatory cytokine responses should be investigated as a cause of IRD.
Plasma But Not Cerebrospinal Fluid Interleukin 7 and Interleukin 5 Levels Pre–Antiretroviral Therapy Commencement Predict Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome
Publisher: Oxford University Press (OUP)
Date: 05-07-2017
DOI: 10.1093/CID/CIX598
Early commencement of antiretroviral therapy in HIV patients from resource-limited countries may prevent the hazards of severe immunodeficiency
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2010
Serum Immune Activation Markers Are Persistently Increased in Patients with HIV Infection after 6 Years of Antiretroviral Therapy despite Suppression of Viral Replication and Reconstitution of CD4+ T Cells
Publisher: Oxford University Press (OUP)
Date: 15-10-2009
DOI: 10.1086/605890
Abstract: The effect of long-term antiretroviral therapy on serum immune activation markers was assessed in a cohort of 63 patients before and after 6 years of boosted lopinavir-based antiretroviral therapy. High levels of most markers were associated with lower CD4(+) T cell counts at baseline and at year 6, with the exception of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4) high levels of sCTLA-4 were associated with higher CD4(+) T cell counts at year 6. Abnormalities of serum immune activation markers persisted after 6 years of ART but probably had different causes. Further investigation of the clinical usefulness of assaying immunoglobulin A, neopterin, and sCTLA-4 levels to assess the effectiveness of treatments for human immunodeficiency virus (HIV) disease are warranted.
CD4+ T-Cell Deficiency in HIV Patients Responding to Antiretroviral Therapy Is Associated With Increased Expression of Interferon-Stimulated Genes in CD4+ T Cells
Publisher: Oxford University Press (OUP)
Date: 17-10-2011
Abstract: Most patients with human immunodeficiency virus (HIV) who remain CD4(+) T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4(+) T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-α), we examined these factors in HIV patients with good or poor CD4(+) T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4(+) T cells of patients with poor CD4(+) T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4(+) T-cell recovery was also associated with CD4(+) T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4(+) T-cell recovery may be adversely affected by the effects of IFN-α, which may be amenable to therapeutic intervention.
The Immunopathogenesis of Immune Reconstitution Inflammatory Syndrome Has Become Clearer, but More Complex
Publisher: Oxford University Press (OUP)
Date: 11-04-2023
TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-07-2011
Leiomyoma of the oesophagus in an HIV-infected patient
Publisher: Wiley
Date: 26-02-2001
DOI: 10.1046/J.1440-1673.2001.00874.X
Abstract: Leiomyomas of the oesophagus are uncommon, and have not been reported in patients infected with the human immunodeficiency virus (HIV). A case of an oesophageal leiomyoma in an adult infected with HIV is presented.
Parvovirus B19 Encephalitis Presenting as Immune Restoration Disease after Highly Active Antiretroviral Therapy for Human Immunodeficiency Virus Infection
Publisher: Oxford University Press (OUP)
Date: 05-2003
DOI: 10.1086/374603
Abstract: Illness occurring during the initial months of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection may be a consequence of the restoration of an immune response against opportunistic pathogens (i.e., immune restoration disease [IRD]). We describe a young man who had AIDS complicated by parvovirus B19 infection and RBC aplasia and who developed a painless, progressive dyspraxia of the left arm and an expressive dysphasia 4 weeks after commencing effective HAART. Neuroimaging demonstrated multiple right fronto-parietal lesions, and, following extensive investigations, including a brain biopsy, it was concluded that the brain lesions represented IRD associated with parvovirus B19 infection.
Immunological Responses to Antiretroviral Therapy
Publisher: Springer New York
Date: 2014
Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JACI.2012.06.023
Abstract: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22 R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5% T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014 odds ratio, 3.64 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells. The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.
Impaired CTLA-4 responses in COPD are associated with systemic inflammation
Publisher: Springer Science and Business Media LLC
Date: 24-03-2014
DOI: 10.1038/CMI.2014.20
Overcoming nitrite oxidizing bacteria adaptation through alternating sludge treatment with free nitrous acid and free ammonia
Publisher: American Chemical Society (ACS)
Date: 14-01-2019
Abstract: Stable suppression of nitrite oxidizing bacteria (NOB) is one of the major bottlenecks for achieving mainstream nitrite shunt or partial nitritation/anammox (PN/A). It is increasingly experienced that NOB could develop resistance to suppressions over an extended time, leading to failure of nitrite shunt or PN/A. This study reports and demonstrates the first effective strategy to overcome NOB adaptation through alternating sludge treatment with free nitrous acid (FNA) and free ammonia (FA). During over 650 days of reactor operation, NOB adaptation to both FNA and FA was observed, but the adaptation was successfully overcome by deploying the alternate treatment strategy. Microbial community analysis showed Nitrospira and Nitrobacter, the key NOB populations in the reactor, have the ability to adapt to FNA and FA, respectively, but do not adapt to the alternation. Stable nitrite shunt with nitrite accumulation ratio over 95% and excellent nitrogen removal were maintained for the last 10 months with only one alternation applied. N
Killer Immunoglobulin-Like Receptor Genotype May Distinguish Immunodeficient HIV-Infected Patients Resistant to Immune Restoration Diseases Associated with Herpes Virus Infections
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2007
Role of monocytes in mediating HIV-specific antibody-dependent cellular cytotoxicity
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.JIM.2012.07.006
Abstract: Antibodies (Abs) that mediate antibody-dependent cellular cytotoxicity (ADCC) activity against HIV-1 are of major interest. A widely used method to measure ADCC Abs is the rapid and fluorometric antibody-dependent cellular cytotoxicity (RFADCC) assay. Antibody-dependent killing of a labelled target cell line by PBMC is assessed by loss of intracellular CFSE but retention of membrane dye PKH26 (CFSE-PKH26+). Cells of this phenotype are assumed to be derived from CFSE+PKH26+ target cells killed by NK cells. We assessed the effector cells that mediate ADCC in this assay. Backgating analysis and phenotyping of CFSE-PKH26+ revealed that the RFADCC assay's readout mainly represents CD3-CD14+ monocytes taking up the PKH26 dye. This was confirmed for 53 HIV+plasma-purified IgG s les when co-cultured with PBMC from three separate healthy donors. Emergence of the CFSE-PKH26+ monocyte population was observed upon co-culture of targets with purified monocytes but not with purified NK cells. Image flow cytometry and microscopy showed a monocyte-specific interaction with target cells without typical morphological changes associated with phagocytosis, suggesting a monocyte-mediated ADCC process. We conclude that the RFADCC assay primarily reflects Ab-mediated monocyte function. Further studies on the immunological importance of HIV-specific monocyte-mediated ADCC are warranted.
Comparison of Etests and Vitek 2® to broth microdilution for the susceptibility testing of Cryptococcus neoformans
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.DIAGMICROBIO.2014.09.006
Abstract: We determined the susceptibility of 102 clinical isolates Cryptococcus neoformans from Durban, South Africa, to hotericin B, fluconazole, flucytosine, and voriconazole using broth microdilution (BMD) according to the Clinical and Laboratory Standards Institute M27-A3 document and compared these results with Etest and Vitek 2(®). Essential agreement (EA) of Etest and Vitek 2(®) compared to BMD was determined. Low MICs that were below the epidemiological cutoff values of the 4 antifungal agents tested were demonstrated by all isolates. The EA of Etests for fluconazole, hotericin, and voriconazole was 95.1%, 83.3%, and 91.2%, respectively, and for Vitek 2(®) EA for fluconazole, hotericin, and flucytosine was 97.1%, 95.1%, and 97.1%, respectively. The Vitek 2(®) showed good agreement with BMD and is a suitable alternative. Etests demonstrated good EA for azoles only. Clinical cryptococcal isolates from Durban remain susceptible to current recommended antifungal therapy.
Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S1386-6532(01)00200-1
Abstract: Some immune defects caused by HIV infection resolve following treatment with highly active antiretroviral therapy (HAART), but residual immune dysfunction may cause disease. Problems with the regulation of the restored immune system in the first six months of treatment can lead to atypical presentations of mycobacterial, cytomegalovirus (CMV), hepatitis B virus or hepatitis C virus (HCV) disease. We defined these conditions as immune restoration diseases (IRD) and showed that they occur in 30-40% of in iduals who begin HAART from low CD4 T cell counts. Analysis of immune dysregulation in patients who have responded to HAART. Patients with successful immune reconstitution following HAART were selected from a database containing details of all patients managed at Royal Perth Hospital (Western Australia) on the basis a CD4 T cell count 4-fold or to >200 CD4 T cells/microl. Patients who had experienced an IRD demonstrated increased levels of bioavailable IL-6 and increased expression of CCR5 and CCR3 on monocytes and granulocytes, but numbers of gammadeltaT-cells were similar to patients with similar CD4 T cell counts without an IRD. Carriage of HLA-A2, -B44 was associated with a history of CMV retinitis and/or encephalomyelitis as an IRD, but not with IRD initiated by Mycobacterium sp., cutaneous varicella zoster or herpes simplex infections or HCV. We also identified a patient with Graves' thyrotoxicosis and pronounced lymphadenopathy after HAART, and demonstrated that thyroid stimulating hormone receptor antibody production was associated with an increase in serum soluble CD30, suggesting acquired immune dysregulation. IRD are associated with persistent immune activation, where differences in genetic profiles suggest that distinct pathological mechanisms are responsible for retinitis/encephalomyelitis IRD. Further studies are important as dysregulated T-cell responses may cause disease later in the course of immune reconstitution.
Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.
Publisher: American Society of Hematology
Date: 24-02-2021
Abstract: The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed s les from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
Cytomegalovirus (CMV) Retinitis Immune Restoration Disease Occurs during Highly Active Antiretroviral Therapy-Induced Restoration of CMV-Specific Immune Responses within a Predominant Th2 Cytokine Environment
Publisher: Oxford University Press (OUP)
Date: 15-06-2002
DOI: 10.1086/340636
Abstract: Plasma levels of cytomegalovirus (CMV)-specific immunoglobulin G (IgG), soluble (s) CD30, sCD26 (dipeptidyl peptidase IV [DPP IV]) enzyme activity, and tumor necrosis factor receptor-I (TNFR-I) were assessed in human immunodeficiency virus (HIV)-infected patients who experienced CMV retinitis (CMVR) as an immune restoration disease (IRD) during their first 6 months of highly active antiretroviral therapy (HAART) and in CMV-seropositive, HIV-infected patients with similar baseline CD4(+) T cell counts who had uneventful immune reconstitution. Patients who experienced CMVR IRD had a significant increase in CMV-specific IgG during their first 12 months of HAART, indicating restored CMV-specific immune responses. They also had significantly higher levels of sCD30 both before HAART and for up to 12 months after start of treatment. sCD30 levels remained elevated during 48 months of HAART, suggesting persistence of a predominant Th2 cytokine environment. Levels of sCD26 (DPP IV) enzyme activity and TNFR-I did not differ significantly between the 2 groups at any time point.
Restoration of CD4 T-cell responses to cytomegalovirus is short-lived in severely immunodeficient HIV-infected patients responding to highly active antiretroviral therapy
Publisher: Wiley
Date: 11-2004
DOI: 10.1111/J.1468-1293.2004.00245.X
Abstract: To define the level of pathogen-specific immune reconstitution persisting over 3 to 5 years of highly active antiretroviral therapy (HAART) in HIV-infected patients who began therapy with CD4 T-cell counts below 50 cells/microL. Cytomegalovirus (CMV)-specific T-cell responses were analysed in adult HIV-1-infected patients with nadir CD4 T-cell counts below 50 cells/microL before HAART. CMV-specific CD4 T-cell responses were measured by interferon-gamma enzyme-linked immunospot assay (ELISpot assay), lymphoproliferation and interferon-gamma levels in cell culture supernatants. CD4 T-cell responses to CMV were low in untreated patients and remained low during the first year on HAART, but increased progressively to levels similar to those found in HIV-seronegative CMV-seropositive controls at 3 years. Responses then declined markedly and at 5 years were lower than controls. This could not be explained by changes in CD4 or CD8 T-cell counts or plasma HIV RNA levels. Interferon-gamma and interleukin-5 responses to a mitogen were maintained or elevated. CMV-specific CD4 T-cell responses were found to decline after 3-5 years on HAART and may provide inadequate long-term protection against CMV disease in patients who are severely immunodeficient prior to treatment.
Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.TUBE.2014.07.002
Abstract: Previous studies suggest that control of Mycobacterium tuberculosis infection is compromised by the activity of regulatory T cells, including those that express CD39, an ectonucleotidase with immunosuppressive properties. Here, we examine the role of CD39 on CD4+ T cells reacting to M. tuberculosis antigens. Cryopreserved PBMC from patients with active TB (n = 31) or in iduals with LTBI (n = 30) were cultured with PPD, ESAT-6 or CFP-10 and antigen-reactive CD4+ T cells assessed by: A) intracellular expression of interferon-gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-2, B) co-expression of CD25 and CD134 with or without CD39, and C) production of IFN-γ, TNF-α and IL-10 in culture supernatants. Active TB patients were not differentiated from in iduals with LTBI by intracellular expression of IFN-γ, TNF-α or IL-2 (alone or together), nor by co-expression of CD25 and CD134. However, active TB patients exhibited higher proportions of CD25+, CD134+, CD4+ T cells expressing CD39 in response to all antigens (p ≤ 0.022). Furthermore, in response to PPD, CD39 expression on CD25+, CD134+, CD4+ T cells correlated with IL-10 production (r = 0.41, p = 0.005) and inhibition of CD39 decreased IL-10 production. Antigen-reactive CD4+ T cells expressing CD39 are more abundant in active TB than LTBI and are associated with production of the immunosuppressive cytokine IL-10. Modulating the effects of CD39 might enhance cellular immune responses against M. tuberculosis.
Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2013
Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies
Publisher: Elsevier BV
Date: 10-2015
Therapeutic CCR5 blockade illuminates IRIS pathogenesis
Publisher: Elsevier BV
Date: 11-2014
Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2010
Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions
Publisher: Elsevier BV
Date: 11-2010
Vaccine-induced IgG2 anti-HIV p24 is associated with control of HIV in patients with a 'high-affinity' FcγRIIa genotype
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2010
Dysregulation of CD28 and CTLA-4 expression by CD4 T cells from previously immunodeficient HIV-infected patients with sustained virological responses to highly active antiretroviral therapy
Publisher: Wiley
Date: 07-2005
DOI: 10.1111/J.1468-1293.2005.00307.X
Abstract: Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/microL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/microL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts 4 years on HAART and >6 months of complete viral suppression ( 1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART.
Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets
Publisher: Rockefeller University Press
Date: 11-07-2016
DOI: 10.1084/JEM.20151467
Abstract: Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying in iduals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation.
Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation
Publisher: Springer Science and Business Media LLC
Date: 2012
Interferon-γ and IL-5 production correlate directly in HIV patients Co-infected with mycobacterium tuberculosis with or without immune restoration disease
Publisher: Mary Ann Liebert Inc
Date: 12-2010
Abstract: IL-5 and interferon-γ responses were investigated in mitogen-stimulated whole-blood cultures from HIV patients with and without Mycobacterium tuberculosis disease, to determine whether an imbalance of Th1/Th2 cytokines contributes to susceptibility to M. tuberculosis disease or to immune restoration disease (IRD) associated with M. tuberculosis after starting antiretroviral therapy (ART). Interferon-γ levels were constant on ART, whilst IL-5 levels generally rose over time. We suggest that increased IL-5 production reflects a recovery of CD4(+) T cell function and that a Th1/Th2 imbalance is not associated with increased susceptibility to M. tuberculosis disease or IRD associated with M. tuberculosis upon starting ART.
Circulating Memory B Cells in Early Multiple Sclerosis Exhibit Increased IgA+ Cells, Globally Decreased BAFF-R Expression and an EBV-Related IgM+ Cell Signature
Publisher: Frontiers Media SA
Date: 16-02-2022
DOI: 10.3389/FIMMU.2022.812317
Abstract: Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology. To further explore this, B cell profiles in peripheral blood from 28 treatment-naive patients with early MS were assessed using flow cytometry and compared to 17 healthy controls. Conventional and algorithm-based analysis revealed a significant increase in MS patients of IgA + memory B cells (MBC) including CD27 + , CD27 - and Tbet + subsets. Screening circulating B cells for markers associated with B cell function revealed a significantly decreased expression of the B cell activation factor receptor (BAFF-R) in MS patients compared to controls. In healthy controls, BAFF-R expression was inversely associated with abundance of differentiated MBC but this was not observed in MS. Instead in MS patients, decreased BAFF-R expression correlated with increased production of proinflammatory TNF following B cell stimulation. Finally, we demonstrated that reactivation of Epstein Barr Virus (EBV) in MS patients was associated with several phenotypic changes amongst MBCs, particularly increased expression of HLA-DR molecules and markers of a T-bet + differentiation pathway in IgM + MBCs. Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation. This study adds further insights into the contribution of B cells to the pathological mechanisms of MS, as well as the complex role of BAFF/BAFF-R signalling in MS.
Characterising the Phenotypic Diversity of Antigen-Specific Memory B Cells Before and After Vaccination
Publisher: Frontiers Media SA
Date: 28-09-2021
DOI: 10.3389/FIMMU.2021.738123
Abstract: The ersity of B cell subsets and their contribution to vaccine-induced immunity in humans are not well elucidated but hold important implications for rational vaccine design. Prior studies demonstrate that B cell subsets distinguished by immunoglobulin (Ig) isotype expression exhibit ergent activation-induced fates. Here, the antigen-specific B cell response to tetanus toxoid (TTd) booster vaccination was examined in healthy adults, using a dual-TTd tetramer staining flow cytometry protocol. Unsupervised analyses of the data revealed that prior to vaccination, IgM-expressing CD27 + B cells accounted for the majority of TTd-binding B cells. 7 days following vaccination, there was an acute expansion of TTd-binding plasmablasts (PB) predominantly expressing IgG, and a minority expressing IgA or IgM. Frequencies of all PB subsets returned to baseline at days 14 and 21. TTd-binding IgG + and IgA + memory B cells (MBC) exhibited a steady and delayed maximal expansion compared to PB, peaking in frequencies at day 14. In contrast, the number of TTd-binding IgM + IgD + CD27 + B cells and IgM-only CD27 + B cells remain unchanged following vaccination. To examine TTd-binding capacity of IgG + MBC and IgM + IgD + CD27 + B cells, surface TTd-tetramer was normalised to expression of the B cell receptor-associated CD79b subunit. CD79b-normalised TTd binding increased in IgG + MBC, but remained unchanged in IgM + IgD + CD27 + B cells, and correlated with the functional affinity index of plasma TTd-specific IgG antibodies, following vaccination. Finally, frequencies of activated (PD-1 + ICOS + ) circulating follicular helper T cells (cT FH ), particularly of the CXCR3 - CCR6 - cT FH 2 cell phenotype, at their peak expansion, strongly predicted antigen-binding capacity of IgG + MBC. These data highlight the phenotypic and functional ersity of the B cell memory compartment, in their temporal kinetics, antigen-binding capacities and association with cT FH cells, and are important parameters for consideration in assessing vaccine-induced immune responses.
Association Between Plasma Antibody Responses and Risk for Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome
Publisher: Oxford University Press (OUP)
Date: 16-07-2018
Abstract: Initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected in iduals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated. We compared plasma levels of immunoglobulins, C. neoformans glucuronoxylomannan (GXM) capsule-specific and laminarin (Lam)-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not, and evaluated associations of these parameters with risk of C-IRIS. Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P = .0003), Lam-IgM (P = .0005), Lam-IgG (P = .002), and GXM-IgM (P = .002) independent of age, sex, HIV viral load, CD4+ T-cell count, and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells. Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.
Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial
Publisher: Elsevier BV
Date: 12-2015
The dynamics of HCV-specific antibody responses in HIV/HCV patients on long-term antiretroviral therapy
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.CLIM.2017.03.005
Abstract: Antibody responses have not been fully characterised in chronically HIV/HCV patients receiving antiretroviral therapy (ART). Seventeen HIV/HCV patients receiving ART were followed for a median (range) interval of 597 (186-766) weeks. Prior to ART, HIV/HCV patients had lower levels of antibodies reactive with HCV core and JFH-1, and lower genotype cross-reactive neutralising antibodies (nAb) titres, than HCV patients. Levels of JFH-1 reactive antibody increased on ART, irrespective of CD4
Energy Performance of Buildings
Publisher: Springer International Publishing
Date: 2016
COVID-19 and HIV-Associated Immune Reconstitution Inflammatory Syndrome: Emergence of Pathogen-Specific Immune Responses Adding Fuel to the Fire
Publisher: Frontiers Media SA
Date: 24-03-2021
DOI: 10.3389/FIMMU.2021.649567
Abstract: Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is lified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4 + T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, lification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the ‘cytokine storm’.
Extremely prolonged HIV seroconversion associated with an MHC haplotype carrying disease susceptibility genes for antibody deficiency disorders
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.CLIM.2010.07.003
Abstract: Severe immunodeficiency during primary human immunodeficiency virus (HIV) infection is unusual. Here, we characterized viral and immunological parameters in a subject presenting with Pneumocystis jirovecii pneumonia in the setting of prolonged primary HIV illness and delayed seroconversion. HIV antibody was only detected by enzyme-linked immunosorbent assay 12 months after presentation, and Western blot profiles remain indeterminate. Isolated virus was of R5 phenotype, exhibited poor viral fitness, but was otherwise unremarkable. Analysis of HIV antibody isotypes showed failure to mount a detectable HIV IgG response over nearly 2 years of infection, in particular IgG(1)- and IgG(3)-specific responses, despite normal responses to common infections and vaccines. Genetic analysis demonstrated homozygosity for part of an MHC haplotype containing susceptibility genes for common variable immunodeficiency (CVID) syndrome and other antibody deficiency disorders. Thus, a primary disorder of specific antibody production may explain exceptionally slow antibody development in an otherwise severe seroconversion illness. This highlights the need for multiparameter testing, in particular use of a fourth generation HIV test, for confirming HIV infection and underscores the importance of host factors in HIV pathogenesis.
Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration
Publisher: Elsevier BV
Date: 12-2016
Immunopathogenesis and Diagnosis of Tuberculosis and Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome during Early Antiretroviral Therapy
Publisher: Oxford University Press (OUP)
Date: 12-2009
DOI: 10.1086/644784
Abstract: In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). We used tuberculin skin testing and the QuantiFERON-TB Gold In-Tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference 1 (RD1) antigens during the first 24 weeks of ART. TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231 (4.8%) participants at risk, respectively. Greater increases in interferon gamma (IFN-gamma) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P< or = .04), respectively. Raw IFN-gamma responses to RD1 antigens and PPD corrected for pre-ART CD4(+) T cell counts were higher at all time points in in iduals with ART-associated tuberculosis (P<.001) and were associated with areas under receiver operator characteristic curves of 0.90 for RD1 (95% confidence interval [CI], 0.78-1.00) and 0.92 for PPD (95% CI, 0.83-1.00) for the diagnosis of ART-associated tuberculosis. Pre-ART IFN-gamma responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30.0%. Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS. IFN-gamma release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.
Higher Levels of CRP, D-dimer, IL-6, and Hyaluronic Acid Before Initiation of Antiretroviral Therapy (ART) Are Associated With Increased Risk of AIDS or Death
Publisher: Oxford University Press (OUP)
Date: 06-2011
Recovery of CD4+ T cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1097/01.QAI.0000188990.57760.E3
Abstract: We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts 400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors.
HIV protease inhibitor substitution in patients with lipodystrophy: A randomized, controlled, open-label, multicentre study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2001
DOI: 10.1097/00002030-200109280-00010
Abstract: Lipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution. Eighty-one HIV protease inhibitor recipients (78 male mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48. There was a greater decline in total body fat in the switch group than in the continue group (-1.6 and -0.4 kg, respectively at week 24 P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter. In predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.
Biomarkers of Inflammation and Coagulation Are Associated With Mortality and Hepatitis Flares in Persons Coinfected With HIV and Hepatitis Viruses
Publisher: Oxford University Press (OUP)
Date: 18-01-2013
On the thermal characteristics and the mitigation potential of a medium size urban park in Athens, Greece
Publisher: Elsevier BV
Date: 03-2014
Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy
Publisher: Oxford University Press (OUP)
Date: 12-06-2013
Transcriptomic Predictors of Paradoxical Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.
Publisher: Oxford University Press (OUP)
Date: 07-2018
DOI: 10.1093/OFID/OFY157
Abstract: Paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) affects ~25% of human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (CM) after they commence antiretroviral therapy (ART) resulting in significant morbidity and mortality. Genomic studies in cryptococcal meningitis and C-IRIS are rarely performed. We assessed whole blood transcriptomic profiles in 54 HIV-infected subjects with CM who developed C-IRIS (27) and compared the results with control subjects (27) who did not experience neurological deterioration over 24 weeks after ART initiation. S les were analyzed by whole genome microarrays. The predictor screening algorithms identified the low expression of the components of interferon-driven antiviral defense pathways, such as interferon-inducible genes, and higher expression of transcripts that encode granulocyte-dependent proinflammatory response molecules as predictive biomarkers of subsequent C-IRIS. Subjects who developed early C-IRIS (occurred within 12 weeks of ART initiation) were characterized by upregulation of biomarker transcripts involved in innate immunity such as the inflammasome pathway, whereas those with late C-IRIS events (after 12 weeks of ART) were characterized by abnormal upregulation of transcripts expressed in T, B, and natural killer cells, such as IFNG, IL27, KLRB1, and others. The AIM2, BEX1, and C1QB were identified as novel biomarkers for both early and late C-IRIS events. An inability to mount effective interferon-driven antiviral immune response, accompanied by a systemic granulocyte proinflammatory signature, prior to ART initiation, predisposes patients to the development of C-IRIS. Although early and late C-IRIS have seemingly similar clinical manifestations, they have different molecular phenotypes (as categorized by bioinformatics analysis) and are driven by contrasting inflammatory signaling cascades.
Interferon-Gamma Responses to Candida Recover Slowly or Remain Low in Immunodeficient HIV Patients responding to ART
Publisher: Springer Science and Business Media LLC
Date: 03-2006
DOI: 10.1007/S10875-006-9008-4
Abstract: Extended assessments of memory T-cell responses in HIV patients who have a satisfactory virological response to combination antiretroviral therapy (CART) have been limited by availability of longitudinal s les and of antigens to which most in iduals (including HIV-negative controls) have been exposed. Studies of cytomegalovirus (CMV) show that interferon-gamma (IFN-gamma) responses never recover completely, but this may be antigen-specific. Here we present responses to Candida and CMV antigens analyzed using a statistical approach that derives overall trends from s les collected at variable time points. Results were considered in relation to putative markers of T-regulatory cells. Blood mononuclear cells collected from seventeen HIV-1 patients (nadir <100 CD4 T cells/mL) 0-8 years after initiation of CART were stimulated with Candida spp lysate, Candida enolase protein or CMV lysate and production of IFN-gamma was assessed by ELISpot assay. CD4 T-cell counts increased fivefold and stabilized within 24 months on CART, following control of plasma viremia. IFN-gamma responses to Candida antigens began low and increased slowly, generating positive slope up to 60 months on CART (Candida enolase p=0.008 Candida lysate p=0.03 mixed-model Wald test). Only two patients displayed a CMV or Candida-specific IFN-gamma response above the median for seronegative controls. Proportions of T cells expressing CD25 or CD57 did not correlate with IFN-gamma responses. Slow reconstitution of IFN-gamma responses to CMV and Candida in previously immunodeficient patients with restored CD4+ T-cell counts on CART suggests a broad and nonresolving defect in memory T-cell responses.
The role of SARS‐CoV ‐2 antibodies in COVID ‐19: Healing in most, harm at times
Publisher: Wiley
Date: 20-05-2020
DOI: 10.1111/RESP.13852
Factors Associated With Plasma IL-6 Levels During HIV Infection
Publisher: Oxford University Press (OUP)
Date: 26-02-2015
Immune reconstitution disease: recent developments and implications for antiretroviral treatment in resource-limited settings
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2007
The effect of combination antiretroviral therapy on CD5 B-cells, B-cell activation and hypergammaglobulinaemia in HIV-1-infected patients
Publisher: Wiley
Date: 09-2005
DOI: 10.1111/J.1468-1293.2005.00312.X
Abstract: This study assessed B-cell activation, CD5 B-cells and circulating immunoglobulin levels in HIV-infected patients treated with combination antiretroviral therapy (CART). Measurement of plasma immunoglobulin levels and electrophoresis of plasma proteins, and analyses of total numbers of B-cells and B-cells expressing CD 38 and CD5 in whole blood, were undertaken in 47 consecutive HIV-1-infected patients attending an out-patient clinic. All HIV-infected patients had similar percentages and numbers of B-cells. Proportions of CD5 B-cells in all HIV-infected patients were significantly lower than those in HIV-negative controls. Aviraemic HIV-infected patients on CART had lower percentages of CD5, CD 38 and CD5 CD 38 B-cell subsets and lower plasma levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) than viraemic HIV-infected patients (untreated or on CART). However, 33-37% of aviraemic HIV-infected patients had IgG and IgA levels above the 95th percentile of the normal range defined in HIV-seronegative donors. In aviraemic HIV-infected patients, plasma IgA levels correlated only with proportions of activated (CD 38) B-cells. IgG levels did not correlate with the proportions of B-cell subsets or any marker of HIV disease activity. Monoclonal immunoglobulins were not detected in any plasma s le. Aviraemic HIV-infected patients on CART have lower plasma levels of IgG and IgA than viraemic HIV-infected patients, but levels are often above the normal range. CD5 B-cell numbers are depressed, so these cells are unlikely to contribute to hypergammaglobulinaemia in HIV-infected patients.
Prospective International Study of Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome and Death in People Living With Human Immunodeficiency Virus and Severe Lymphopenia
Publisher: Oxford University Press (OUP)
Date: 05-09-2020
DOI: 10.1093/CID/CIZ877
Abstract: Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. We investigated the clinical impact of IRIS in PLWH and CD4 counts & cells/μL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/μL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2 P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2 P = .031). Being female (P = .004) and having a lower body mass index (BMI P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin & .5 g/dL as predictive of IRIS and C-reactive protein (CRP) & μg/mL and BMI & .6 kg/m2 as predictive of death. For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk.
Intensification of Antiretroviral Therapy With Raltegravir or Addition of Hyperimmune Bovine Colostrum in HIV-Infected Patients With Suboptimal CD4(+) T-Cell Response: A Randomized Controlled Trial
Publisher: Oxford University Press (OUP)
Date: 19-09-2011
Abstract: Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients. We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods. Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27 20.45, P = .724 and 9.43 cells/μL, -7.81 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA. The determinants of poor CD4(+) T-cell recovery following cART require further investigation. ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.
Robust interferon-α and IL-12 responses by dendritic cells are related to efficient CD4+ T-cell recovery in HIV patients on ART
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.CLIM.2011.02.015
Abstract: Amongst HIV patients with successful virological responses to antiretroviral therapy (ART), poor CD4(+) T-cell recovery is associated with low nadir CD4(+) T-cell counts and persistent immune activation. These factors might be influenced by dendritic cell (DC) function. Interferon-α-producing plasmacytoid DC and IL-12-producing myeloid DC were quantified by flow cytometry after stimulation with agonists to TLR7/8 (CL075) or TLR9 (CpG-ODN). These were compared between patients who achieved CD4(+) T-cell counts above or below 200 cells/μL after 6 months on ART (High vs. Low groups). High Group patients had more DC producing interferon-α or IL-12 at Weeks 6 and 12 on ART than Low Group patients. The frequencies of cytokine-producing DC at Week 12 were directly correlated with CD4(+) T-cell counts at baseline and at Week 12. Patients with good recovery of CD4(+) T-cells had robust TLR-mediated interferon-α responses by plasmacytoid DC and IL-12 responses by myeloid DC during early ART (1-3 months).
Viremic HIV Controllers Exhibit High Plasmacytoid Dendritic Cell–Reactive Opsonophagocytic IgG Antibody Responses against HIV-1 p24 Associated with Greater Antibody Isotype Diversification
Publisher: The American Association of Immunologists
Date: 06-2015
Abstract: Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG Abs against HIV-1 Gag proteins (e.g., p24) and/or production of IgG2 Abs against HIV-1 proteins. These Abs likely exert their effect by activating antiviral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG Ab response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by Ab isotype ersification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG Ab responses against HIV-1 p24 were higher in HIV controllers (HIV RNA & 2000 copies/ml) than noncontrollers (HIV RNA & 10,000 copies/ml), particularly in controllers with low but detectable viremia (HIV RNA 75–2000 copies/ml). Opsonophagocytic Ab responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and, notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these Abs was mediated via FcγRIIa. Isotype ersification (toward IgG2) was greatest in HIV controllers, and depletion of IgG2 from Ig preparations indicated that IgG2 Abs to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of Ab function, such as Ag opsonization. Our findings emulate those for pDC-reactive opsonophagocytic Ab responses against coxsackie, picorna, and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.
Impaired Upregulation of the Costimulatory Molecules, CD27 and CD28, on CD4+ T Cells from HIV Patients Receiving ART Is Associated with Poor Proliferative Responses
Publisher: Mary Ann Liebert Inc
Date: 02-2017
Immune Activation in Patients Infected with HIV Type 1 and Maintaining Suppression of Viral Replication by Highly Active Antiretroviral Therapy
Publisher: Mary Ann Liebert Inc
Date: 10-12-2002
DOI: 10.1089/088922202320935429
Abstract: Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of 6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.
The frequency of high-grade intraepithelial neoplasia in anal/perianal warts is higher than previously recognized
Publisher: SAGE Publications
Date: 08-2007
DOI: 10.1258/095646207781439694
Abstract: A retrospective review of the prevalence of intraepithelial neoplasia (IN) in surgically removed perianal/anal warts from December 1995 to December 2004 was undertaken in patients referred to the Sexual Health Clinic at Royal Perth Hospital. Data were analysed from 115 men and 38 women, 29 of whom had HIV infection (27 men and two women). Perianal/anal IN within the warts was found in 78% (52% high grade) of men with HIV infection. In men without HIV infection, the overall rate of IN within warts was 33% (20% high grade). The IN rate was 8.3% for HIV-negative women (2.8% high grade). Rates of IN within perianal/anal warts in men with or without HIV infection are higher than previously reported, and suggest the likelihood of a substantial increase in the future incidence of anal cancer. The association between IN and genital warts needs to be further studied.
Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis
Publisher: Springer Science and Business Media LLC
Date: 04-03-2021
DOI: 10.1038/S41598-021-84881-8
Abstract: Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood s les taken at first presentation of Clinically Isolated Syndrome (CIS an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.
Chronic HIV-1 infection induces B-cell dysfunction that is incompletely resolved by long-term antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2016
Immune reconstitution inflammatory syndrome: Immune restoration disease 20 years on
Publisher: Wiley
Date: 03-2012
DOI: 10.5694/MJA12.10089
Abstract: Restoration of immune responses against opportunistic pathogens after commencing antiretroviral therapy (ART) may cause immune restoration disease (IRD) in about 10%-40% of HIV patients with low CD4(+) T-cell counts and usually presents clinically as a type of immune reconstitution inflammatory syndrome (IRIS). IRIS may be associated with many different opportunistic pathogens, but types associated with Mycobacterium tuberculosis, BCG, cryptococci, JC polyomavirus (the cause of progressive multifocal leukoencephalopathy [PML]), hepatitis C virus and hepatitis B virus infection are the most informative about disease pathogenesis and management. A CD4(+) T-cell count of < 50/μL and a high pathogen load are the most commonly identified risk factors for IRIS. Recovery of pathogen-specific T-cell responses and perturbations of innate immune responses before and after ART appear to cause immunopathological abnormality in tissues infected by the pathogen. Prevention of IRIS may be influenced by the timing of ART: The risk of tuberculosis (TB)-associated-IRIS can be reduced by commencing ART after 8 weeks of TB treatment, but rates of AIDS or death are lower if ART is commenced during the first 4 weeks of TB treatment. Outcomes for patients with HIV and treated cryptococcal or TB meningitis may be improved by deferring ART until the opportunistic infection is fully suppressed, but data are inadequate. As ART is currently the only effective treatment for PML in patients with HIV, PML-associated IRIS cannot be prevented by manipulating the timing of ART. A greater understanding of the immunopathogenesis of IRIS may lead to targeted therapies.
The immunopathogenesis of mycobacterial immune restoration disease
Publisher: Elsevier BV
Date: 08-2006
Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS+ circulating memory T follicular-helper cells which is impaired by HIV infection
Publisher: Public Library of Science (PLoS)
Date: 02-05-2017
Inferior Clinical Outcome of the CD4+ Cell Count–Guided Antiretroviral Treatment Interruption Strategy in the SMART Study: Role of CD4+ Cell Counts and HIV RNA Levels during Follow-up
Publisher: Oxford University Press (OUP)
Date: 15-04-2008
DOI: 10.1086/529523
Abstract: Background and methodsThe SMART study compared 2 strategies for using antiretroviral therapy—drug conservation (DC) and viral suppression (VS)—in 5472 human immunodeficiency virus (HIV)–infected patients with CD4+ cell counts & cells/μL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported ResultsDuring a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count & cells/μL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level & copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow-up with a CD4+ cell count & cells/μL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years RR, 2.3 [95% confidence interval, 1.5–3.4]) for periods with the latest CD4+ cell count ⩾350 cells/μL—an increase explained by the higher HIV RNA levels in the DC group ConclusionsThe higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death Trial registrationClinicalTrials.gov identifier: NCT00027352
Integrated Evaluation of the Performance of Composite Cool Thermal Insulation Materials
Publisher: Elsevier BV
Date: 11-2015
FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis
Publisher: Frontiers Media SA
Date: 11-01-2021
DOI: 10.3389/FIMMU.2020.614492
Abstract: B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM + B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM + B cell subsets, including naive and IgM hi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgM hi MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.
Short Communication: Plasma Levels of Vitamin D in HIV Patients Initiating Antiretroviral Therapy Do Not Predict Immune Restoration Disease Associated with Mycobacterium tuberculosis
Publisher: Mary Ann Liebert Inc
Date: 10-2012
Plasma Bioavailable Interleukin-6 Is Elevated in Human Immunodeficiency Virus-Infected Patients Who Experience Herpesvirus-Associated Immune Restoration Disease after Start of Highly Active Antiretroviral Therapy
Publisher: Oxford University Press (OUP)
Date: 15-10-2001
DOI: 10.1086/323599
Abstract: This study compared plasma bioavailable interleukin (IL)-6 levels in 3 groups: human immunodeficiency virus (HIV)-infected patients who had a human herpesvirus (HHV)-associated immune restoration disease (IRD) during highly active antiretroviral therapy (HAART) patients who experienced an IRD initiated by Mycobacterium avium complex, hepatitis C virus, or human papillomavirus and control patients who had uneventful immune reconstitution. Total IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 were measured by ELISA, and levels of free IL-6 and sIL-6/IL-6R complex were modeled mathematically. Persons who had an HHV-associated IRD had increased plasma bioavailable IL-6 before HAART, compared with patients who experienced a non-HHV-associated IRD and with control patients, and their plasma bioavailable IL-6 increased progressively over 3-4 years of treatment. Increased IL-6 production may be a feature of HAART-induced restoration of immune responses to HHV infections and may have long-term immunopathologic consequences.
Perinatal HIV transmission and pregnancy outcomes in indigenous women in Western Australia
Publisher: Wiley
Date: 14-09-2007
Immune restoration disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2008
Novel Sensitive Real-Time PCR for Quantification of Bacterial 16S rRNA Genes in Plasma of HIV-Infected Patients as a Marker for Microbial Translocation
Publisher: American Society for Microbiology
Date: 10-2011
DOI: 10.1128/JCM.01018-11
Abstract: We developed a real-time PCR to quantify 16S rRNA gene levels in plasma from HIV-infected patients as a marker of microbial translocation. The assay uses shrimp nuclease (SNuc) to eliminate DNA contamination, giving high sensitivity and low variability. The 16S rRNA gene levels measured in plasma from HIV patients correlated significantly with lipopolysaccharide levels.
Intraoperative dexamethasone alters immune cell populations in patients undergoing elective laparoscopic gynaecological surgery
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1093/BJA/AEX154
Abstract: Anaesthetists use dexamethasone principally for its anti-emetic effect. The purpose of this study was to characterize the effects of a single intraoperative dose of dexamethasone on cellular and metabolic components of the immune system in patients undergoing laparoscopic surgical procedures. In this prospective double-blind trial, female patients undergoing elective major laparoscopic surgery were randomized to receive saline (Control group, n =16) or dexamethasone 4 mg (Dexamethasone group, n =16) i.v. after the induction of anaesthesia. Inflammatory markers and immune cell counts were examined at 24 and 48 h and 6 weeks after surgery. The changes from baseline preoperative values were compared between groups using a Mann-Whitney U -test, and linear mixed models were used to validate the findings. No differences in concentrations of serum glucose and interleukin-6 were observed between groups after surgery. The increase in C-reactive protein concentration at 24 h after surgery was greater in the control group [median (interquartile range), 33 (25-65) vs 17 (7-26) mg dl -1 P =0.018]. Extensive changes in the counts of white cells, including most lymphocyte subsets, were observed 24 h after surgery, and dexamethasone appeared to attenuate most of these changes. Changes at 48 h and 6 weeks did not differ between groups. In female patients undergoing elective laparoscopic gynaecological surgery, dexamethasone administration appears to attenuate inflammation and to alter immune cell counts at 24 h, with no effects identified after this time. The importance of these changes for postoperative immune function is unknown. Australia and New Zealand Clinical Trials Registry (ACTRN12608000340336).
Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-07-2007
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
Publisher: Rockefeller University Press
Date: 11-11-2013
DOI: 10.1084/JEM.20130323
Abstract: Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5 ERK PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.
Intrafamilial transmission of HIV-1 infection from individuals with unrecognised HIV-1 infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2003
DOI: 10.1097/00002030-200309050-00017
Abstract: To describe the clinical, epidemiological and molecular evidence for transmission of HIV-1 infection from a person with unrecognized HIV infection to a family member in two unconnected families where the route of transmission could not be conclusively determined. Case studies, molecular analysis of viral strains and a clinical and laboratory investigation of risk factors for transmission. State referral centres for HIV/AIDS in two Australian teaching hospitals. Previously unrecognized HIV-1 infection was diagnosed in two unconnected females following blood donation in different Australian cities. Initially, no source of infection was identified but subsequently HIV-1 infection was diagnosed in the sister of one case and the adult son of the other. Using nucleic acid-based methods, it was demonstrated that one index case and her sister were infected with highly homologous 'Russian-type' HIV-1 subtype A, and the other index case and her son were infected with highly homologous HIV-1 subtype E (CRF01_AE). Sexual history taking from the sister and the son of the respective index cases revealed prior sexual partners from geographical areas in which the corresponding subtypes are known to be prevalent. Extensive history taking, cross-validated by independent reviewers, found no evidence whatsoever that any form of sexual contact or known blood contact could explain the HIV-1 infection in the two index cases. However, there was evidence that some form of domestic contact involving unperceived blood transfer may have occurred. Intra-familial transmission of HIV-1 infection should be considered when a source of HIV-1 infection cannot be determined.
Genetic and Functional Analysis of R5X4 Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Derived from Two Individuals Homozygous for the CCR5Δ32 Allele
Publisher: American Society for Microbiology
Date: 04-2006
DOI: 10.1128/JVI.80.7.3684-3691.2006
Abstract: We characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) isolated from two HIV-1-infected CCR5Δ32 homozygotes. Envs from both subjects used CCR5 and CXCR4 for entry into transfected cells. Most R5X4 Envs were lymphocyte-tropic and used CXCR4 exclusively for entry into peripheral blood mononuclear cells (PBMC), but a subset was dually lymphocyte- and macrophage-tropic and used either CCR5 or CXCR4 for entry into PBMC and monocyte-derived macrophages. The persistence of CCR5-using HIV-1 in two CCR5Δ32 homozygotes suggests the conserved CCR5 binding domain of Env is highly stable and provides new mechanistic insights important for HIV-1 transmission and persistence.
Activation and Coagulation Biomarkers Are Independent Predictors of the Development of Opportunistic Disease in Patients with HIV Infection
Publisher: Oxford University Press (OUP)
Date: 15-09-2009
DOI: 10.1086/605447
Interferon-alpha, immune activation and immune dysfunction in treated HIV infection
Publisher: Wiley
Date: 02-2014
DOI: 10.1038/CTI.2014.1
Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.PLEFA.2018.11.004
Abstract: The synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. Thirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood s les were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. There was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%-50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. This is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period.
Immunopathogenesis of Hepatic Flare in HIV/Hepatitis B Virus (HBV)–Coinfected Individuals after the Initiation of HBV‐Active Antiretroviral Therapy
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1086/597276
Abstract: The pathogenesis of and risk factors for hepatic flare (HF) after the initiation of hepatitis B virus (HBV)-active antiretroviral therapy (ART) in HIV/HBV-coinfected in iduals is not well understood. We studied HF in ART-naive HIV/HBV-coinfected in iduals in Thailand (n = 36) who were beginning HBV-active ART as part of a prospective clinical trial. HF was defined as an alanine aminotransferase (ALT) level>5 times the upper limit of normal or >200 IU/L higher than that at baseline. Immune mediators (interleukin [IL]-18, IL-2, IL-6, IL-8, IL-10, soluble CD26 [sCD26], sCD30, sCD8, CXCL-10, CCL-2, tumor necrosis factor-alpha, interferon [IFN]-gamma, and IFN-alpha) and activated NK cells were quantified. HBV DNA and ALT levels at baseline were higher in patients with HF (n=8) than in patients without HF (n=28) (P=.01). After the initiation of ART, CXCL-10 levels remained elevated in patients with HF but decreased in patients without HF (P<.01). sCD30 levels increased and were significantly higher at week 8 in patients with HF (P<.05). There was a positive correlation between levels of ALT and levels of CXCL-10, sCD30, CCL-2, and IL-18 at week 8 (the time of peak ALT level) but not at other time points. Elevated HBV DNA and ALT levels before the initiation of HBV-active ART are risk factors for HF. The pathogenesis of HF after the initiation of HBV-active ART is probably consistent with immune restoration disease.
Audit of paired anal cytology and histopathology outcomes in patients referred to a public sexual health clinic
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/SH09118
Abstract: Background: The level of agreement between anal cytology and histopathology is not clear with only a few studies evaluating the reliability of anal specimen reporting. Australian data in relation to this are limited. Methods: The results of paired anal cytology and histopathology specimens received between 2002 and 2008 from patients who were referred within the sexual health clinic were retrieved from the anatomical pathology database. A total of 248 paired s les from 154 (21 females, 133 males) participants were extracted. Concurrent high risk human papilloma virus (hrHPV) DNA assay and HIV status for the study group were also collected. Data were tabulated according to reported grade of squamous abnormality based on the Bethesda system. Using the biopsy result as the gold standard the specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) for cytology were calculated and the association between grade of abnormality, HIV status and hrHPV infection estimated. Results: Concordance between cytology and histology showed that in 204 (85%) paired s les both tests were categorised as abnormal (Kappa statistic 0.73, P = 0.013). The cytology result showed a sensitivity of 96%, specificity 14%, PPV 89% and NPV 31% when compared with histopathology. HrHPV assay was positive in 192 (80%) s les. High-grade squamous abnormalities were reported in biopsy specimens from 60% (n = 42/67) of HIV-positive subjects and 25% (n = 22/87) of HIV-negative subjects. HIV-positive in iduals were more likely to be hrHPV positive, odds ratio (OR) 6.21 [95% confidence interval (CI) 2.69 to 14.34], when compared with HIV-negative subjects. Conclusion: Anal cytology is highly sensitive for the detection of abnormal squamous cells. While cytology has low specificity for predicting the grade of abnormality compared with biopsy outcome, its application as a screening method in asymptomatic at risk populations warrants further study.
Impaired function of regulatory T-cells in patients with chronic obstructive pulmonary disease (COPD)
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.IMBIO.2014.07.005
Abstract: Anti-inflammatory pathways affecting chronic obstructive pulmonary disease (COPD) are poorly understood. Regulatory T-cells (Tregs) are important negative regulators of T-cell activity and hence were investigated in COPD patients in this study. We hypothesised that functional defects in Tregs may promote increased inflammation contributing to the pathogenesis of COPD. Peripheral blood mononuclear cells (PBMC) were isolated from patients with stable COPD and age-matched non-smoking controls. Treg-mediated suppression of memory non-Treg (Foxp3(-)CD45RO(+)) CD4(+) T-cell activation was analysed by comparing PBMC responses to staphylococcal enterotoxin-B (SEB) pre- and post-depletion of Tregs (CD25(+)CD127(low)CD4(+) T-cells) by fluorescence-activated cell sorting (FACS). Activation of T-cells was assessed by HLA-DR expression. Levels of secreted cytokines were measured by ELISA. Depletion of Tregs increased SEB-induced activation of Foxp3(-)CD45RO(+) CD4(+) T-cells in s les from 15/15 healthy controls (demonstrating Treg-mediated suppression) and 9/14 COPD patients (Fisher's test, p=0.017). A screen of clinical data associated a failure of Treg-mediated suppression in the remaining five COPD patients with a higher body mass index (BMI) (33-38 kg/m(2)) compared to patients with unimpaired Treg function (20-32 kg/m(2)). In conclusion, we demonstrate impaired Treg-mediated suppression of CD4(+) T-cell activation in a subset of COPD patients, all of whom had high BMI. Obesity and/or perturbed homeostasis of Treg subsets may explain this defect and therefore contribute to increased inflammation observed in COPD.
Audit of emergency department assessment and management of patients presenting with community-acquired needle stick injuries
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/AH09846
Abstract: Objectives. To describe characteristics and management of people with community acquired needle stick injuries (CANSI) attending urban emergency departments and suggest a guideline to improve assessment, management, and documentation. Methods. A retrospective analysis of cases with CANSI attending emergency departments in two tertiary hospitals between 2001 and 2005 using medical record review with follow up phone and written survey. Results. Thirty-nine cases met the criteria for CANSI. Persons younger than 30 years sustained 48.72% of all injuries. Source serology was available for only five cases (12.82%). Thirty-one of thirty-nine patients (79.49%) were classed as not immune to hepatitis B but only four of these (12.90%) received both hepatitis B vaccination and hepatitis B immunoglobulin. Six patients (15.38%) received HIV prophylaxis of which two (33.33%) did not receive baseline HIV testing. Of ten patients referred to immunology clinic for follow up only two (20.00%) attended at 6 months. Conclusion. We have identified groups that are at high risk of CANSI, including young males, security workers and cleaners. In the majority of cases protection against hepatitis B was inadequately provided, and a substantial proportion had inadequate baseline assessment and documentation. A guideline is suggested that may be used to improve these deficits. What is known about this topic? Occupationally acquired needle stick injury guidelines are well established, but no guidelines currently exist for community acquired needle stick injuries (CANSI) which may require different risk stratification, assessment and management. Management of CANSI in Emergency Departments has not been well described. What does this paper add? An audit of Emergency Department management of community acquired needle stick injuries demonstrates deficits in risk assessment, documentation and use of post-exposure immunisation and prophylaxis. A guideline is suggested that may be used to improve these deficits. What are the implications for practitioners? Practitioners need to perform and document a risk assessment of the injury, perform baseline serology, and provide tetanus and hepatitis B immunisation. Use of HIV post-exposure prophylaxis is determined by local prevalence of disease, injury risk assessment, source serology if known, and time since injury.
Immune Restoration Disease Associated with Leishmania donovani Infection following Antiretroviral Therapy for HIV Infection
Publisher: Elsevier BV
Date: 02-2010
Immune Restoration Disease: A Consequence of Dysregulated Immune Responses After HAART
Publisher: Bentham Science Publishers Ltd.
Date: 07-2004
Abstract: Immune Restoration Diseases (IRD) are a collection of atypical 'opportunistic infections' and inflammatory diseases seen in human immunodeficiency virus (HIV) patients after HIV viraemia is suppressed by highly active antiretroviral therapy (HAART). IRD probably reflect dysregulated immune responses against pre-existing infections by opportunistic pathogens, with different immunopathological mechanisms for different pathogens. For ex le, mycobacterial IRD are associated with delayed type hypersensitivity (DTH) responses to mycobacterial antigens, whereas patients who experience cytomegalovirus (CMV) IRD have elevated plasma levels of soluble CD30, a marker of a T2 cytokine environment expressed by activated CD8 T-cells. As IRD are often compartmentalised to organs, monitoring serological markers such as pathogen-specific IgG antibody, may be informative, as demonstrated for CMV and hepatitis C virus (HCV)-associated IRD. Genetic studies have provided evidence of distinct immunopathological mechanisms and inherited susceptibility to IRD associated with mycobacterial and herpesviridae infections. The expansion of HAART in the developing world where many HIV patients have low CD4+ T-cell counts and high rates of concomitant infections will place a large number of patients at-risk of developing IRD. It is therefore important to understand the immunopathology so that prevention, diagnosis and treatment can be improved.
Plasma levels of cytokines and chemokines and the risk of mortality in HIV-infected individuals: A case-control analysis nested in a large clinical trial
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-04-2015
Central MHC genes affect IgA levels in the human: reciprocal effects in IgA deficiency and IgA nephropathy
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0198-8859(02)00383-X
Abstract: This study investigates the hypothesis that alternative alleles of one or more genes in the central major histocompatibility complex (MHC) predispose carriers to IgA deficiency (IgAD) or IgA Nephropathy (IgAN). Australian caucasian IgAD, IgAN patients, and controls were typed at HLA loci, single nucleotide polymorphisms, and microsatellites in the MHC. Alleles of the D6S273 microsatellite exhibited strong associations with IgAD and IgAN. D6S273*129 and *139 were more frequent in IgAD and less frequent in IgAN patients than controls. The reverse was true for D6S273*133 and *131. Alleles of other microsatellites exhibited weak associations with IgAD or IgAN. D6S273*129 is found on the 65.1 ancestral haplotype [HLA-B14(65),DR1], which has been reported to be increased in IgAD, but the majority of IgAD patients with D6S273*129 did not have other alleles of the haplotype. D6S273*139 is characteristic of the 8.1 ancestral haplotype (HLA-A1,B8,DR3), which was common in IgAD and rare in IgAN patients. Further studies of the 8.1 haplotype in Australian, German and Spanish caucasian subjects revealed that HLA-DR3, in the absence of -B8, is not associated with IgAD. However -B8 is associated with IgAD in the absence of -DR3, consistent with a susceptibility locus in the central MHC. Provisional mapping within this region is discussed.
Short-term changes in frequencies of circulating leukocytes associated with narrowband UVB phototherapy in people with clinically isolated syndrome
Publisher: Springer Science and Business Media LLC
Date: 28-05-2019
DOI: 10.1038/S41598-019-44488-6
Abstract: Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty in iduals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood s les for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated in iduals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further.
Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome Is Associated With Dysregulation of IL-7/IL-7 Receptor Signaling Pathway in T Cells and Monocyte Activation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2019
Plasma biomarkers in the prediction and diagnosis of tuberculosis-associated immune reconstitution inflammatory syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2011
Interleukin-7 signalling defects in naive CD4+ T cells of HIV patients with CD4+ T-cell deficiency on antiretroviral therapy are associated with T-cell activation and senescence
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-03-2014
Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.AJO.2017.02.018
Abstract: To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 months. Phase 1 dose escalation trial. Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-corrected visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 10 Six of the 8 subjects completed the 36-month study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were observed during the long-term follow-up period. Exploratory data analysis suggests stability of wet AMD over the 36-month period. Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favourable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.
Major Clinical Outcomes in Antiretroviral Therapy (ART)–Naive Participants and in Those Not Receiving ART at Baseline in the SMART Study
Publisher: Oxford University Press (OUP)
Date: 15-04-2008
DOI: 10.1086/586713
Abstract: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death) (ii) OD (fatal or nonfatal) (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths and (iv) the composite of outcomes (ii) and (iii). A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56 p=.02) outcome (ii), 3.26 (95% CI, 1.04-10.25 p=.04) outcome (iii), 7.02 (95% CI, 1.57-31.38 p=.01) and outcome (iv), 4.19 (95% CI, 1.69-10.39 p=.002 ). Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.
Individuals with HIV-1 Subtype C Infection and Cryptococcal Meningitis Exhibit Viral Genetic Intermixing of HIV-1 between Plasma and Cerebrospinal Fluid and a High Prevalence of CXCR4-Using Variants
Publisher: Mary Ann Liebert Inc
Date: 07-2018
Graves' Disease during Immune Reconstitution after Highly Active Antiretroviral Therapy for HIV Infection: Evidence of Thymic Dysfunction
Publisher: Mary Ann Liebert Inc
Date: 02-2004
DOI: 10.1089/088922204773004879
Abstract: A patient with HIV infection who experienced immune reconstitution after highly active antiretroviral therapy (HAART) [increase in CD4 T cell count from 600/microl] presented with severe Graves' disease 32 months after commencing HAART. A comprehensive clinical and laboratory study demonstrated pronounced regional lymphadenopathy and thymic enlargement at presentation, and that the onset of thyrotropin receptor antibody production was associated with increased production of soluble CD30 (a marker of type 2 immune responses). Blood naive CD8 T cell counts and TREC levels in both CD4 and CD8 T cells were increased at multiple time points compared with carefully selected controls. We conclude that the Graves' disease in this patient was associated with abnormally high blood counts of thymus-derived T cells, and propose that Graves' disease after HAART in this and other HIV patients may result from failure to delete autoreactive T cell clones in the regenerating thymus.
Cytomegalovirus (CMV)-specific CD8+ T cells in individuals with HIV infection: correlation with protection from CMV disease
Publisher: Oxford University Press (OUP)
Date: 27-02-2006
DOI: 10.1093/JAC/DKL049
Abstract: CD8+ cytotoxic T cells play a key role in immunological protection from clinical cytomegalovirus (CMV) disease. Numbers of CMV-specific CD8+ T cells are increased in untreated and antiretroviral-treated HIV patients compared with healthy controls. Accumulation of CMV-specific CD8+ T cells during HIV infection may reflect persistent reactivation of CMV owing to suboptimal immune control and/or oligoclonal expansion of the limited populations of CMV-specific CD8+ T cells present before antiretroviral therapy (ART). CD8+ T cells directed against the CMV immediate early (IE)-1 protein may play an important role in preventing CMV replication to pathogenic levels. However, immunological protection from CMV disease in HIV-infected in iduals on ART does not appear to depend on total numbers of CMV-specific CD8+ T cells but rather on the presence of both effector-memory and effector CMV-specific CD8+ T cells that produce interferon-gamma and/or perforin in response to CMV antigens.
IFN-alpha exerts opposing effects on activation-induced and IL-7-induced proliferation of T cells that may impair homeostatic maintenance of CD4+ T cell numbers in treated HIV infection
Publisher: The American Association of Immunologists
Date: 09-2014
Abstract: To determine whether IFN-α is a cause of the T cell hyperactivation and IL-7 signaling pathway defects that are observed in some HIV patients receiving antiretroviral therapy, we have investigated the effect of IFN-α on the proliferation of CD4+ and CD8+ T cells from healthy donors (n = 30) and treated HIV+ donors (n = 20). PBMC were cultured for 7 d with staphylococcal enterotoxin B or IL-7 in the absence or presence of 100 U/ml IFN-α8. Total and naive CD4+ and CD8+ T cells were assessed for proliferation (via Ki67 expression), CD127 expression, and phosphorylated STAT5 levels using flow cytometry. IFN-α significantly enhanced activation-induced proliferation (via staphylococcal enterotoxin B stimulation) but inhibited homeostatic proliferation (IL-7 induced) of CD4+ and CD8+ T cells. Both of these effects may adversely affect CD4+ T cell homeostasis in HIV patients. CD127 expression was increased in both healthy and HIV+ donors following culture with IFN-α8, and levels of IL-7–induced phosphorylated STAT5 were increased by IFN-α8 in healthy donors only. Hence, the inhibitory effects of IFN-α on IL-7–induced proliferation of CD4+ T cells are unlikely to be mediated by downregulation of CD127 expression or inhibition of STAT5 phosphorylation. These data suggest that increased IFN-α activity may promote the loss of T cells by accelerating cell turnover and activation-induced cell death while decreasing the renewal of T cells by inhibiting the proliferative effect of IL-7.
Control of early HIV-1 infection associates with plasmacytoid dendritic cell-reactive opsonophagocytic IgG antibodies to HIV-1 p24
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-11-2016
Mycobacterium avium Infection and Immune Restoration Disease After Highly Active Antiretroviral Therapy in a Patient with HIV and Normal CD4+ Counts
Publisher: Springer Science and Business Media LLC
Date: 17-11-2001
DOI: 10.1007/S10096-001-0634-8
Abstract: A patient infected with HIV who had normal CD4+ T-cell counts developed Mycobacterium avium complex lymphadenitis associated with restoration of delayed-type hypersensitivity responses to mycobacterial antigens after commencing highly active antiretroviral therapy (Mycobacterium avium immune restoration disease). This case provides further evidence that delayed-type hypersensitivity responses and CD4+ T-cell counts are independent indicators of the cellular immune defects induced by HIV infection and that Mycobacterium avium immune restoration disease may occur in patients with persistently normal CD4+ T-cell counts.
CD4+ and CD8+ T cells expressing FoxP3 in HIV-infected patients are phenotypically distinct and influenced by disease severity and antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2009
A T2 cytokine environment may not limit T1 responses in human immunodeficiency virus patients with a favourable response to antiretroviral therapy
Publisher: Wiley
Date: 22-06-2006
Immune Reconstitution Inflammatory Syndrome: A Reappraisal
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1086/595006
Abstract: In iduals with human immunodeficiency virus infection who commence antiretroviral therapy when they are very immunodeficient are susceptible to immune reconstitution disorders. The most common disorders are the various forms of immune restoration disease (IRD) that appear to result from the restoration of a dysregulated immune response against pathogen-specific antigens. Essentially, any pathogen that can cause an opportunistic infection as a result of cellular immunodeficiency can provoke IRD when pathogen-specific immune responses recover during antiretroviral therapy. In resource-poor countries, Mycobacterium tuberculosis and Cryptococcus neoformans are the most significant pathogens, because the former causes substantial morbidity and the latter causes substantial mortality. IRD associated with these pathogens is characterized by severe inflammatory responses and is often referred to as immune reconstitution inflammatory syndrome. Prevention and treatment strategies for IRD are being developed, but preliminary data have demonstrated the efficacy of corticosteroid therapy in severe cases. Immune reconstitution after antiretroviral therapy may also be associated with autoimmune disease or sarcoidosis, both of which appear to have an immunopathogenesis that is different from that of IRD.
Elevated plasma soluble CD14 and skewed CD16+ monocyte distribution persist despite normalisation of soluble CD163 and CXCL10 by effective HIV therapy: A changing paradigm for routine HIV laboratory monitoring?
Publisher: Public Library of Science (PLoS)
Date: 29-12-2014
IL-23 and IFN-γ deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on highly active antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1097/00002030-200406180-00014
Abstract: The pathogenesis of HIV infection and the susceptibility to opportunistic infections has been associated with poor type 1 cytokine production. In severely immunodeficient HIV patients who achieved increased CD4 T-cell counts on longterm highly active antiretroviral therapy, we observed reduced expression of IL-23p19 and IFN-gamma messenger RNA. Impaired IL-23-induced IFN-gamma production by memory T cells might thus contribute to opportunistic infections in a minority of patients with substantial CD4 T-cell recovery.
Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8 + T-cell memory formation and function
Publisher: Elsevier BV
Date: 08-2013
B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans
Publisher: Rockefeller University Press
Date: 04-01-2010
DOI: 10.1084/JEM.20091706
Abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
HIV and aging: An overview of an emerging issue
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/SH11110
Abstract: Age related morbidity among people living with HIV has increased as people with the virus live longer. This introduction provides an overview of all the articles which cover a spectrum of issues including particular diseases, the science of immunosenescence and the psycho-social challenges of ageing with HIV. It considers whether a syndrome of accelerated ageing exists among people with HIV finding that evidence is currently lacking to support this theory.
Compartmentalization of the immune response in varicella zoster virus immune restoration disease causing transverse myelitis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2004
Peyronie's disease in men with HIV responding to highly active antiretroviral therapy
Publisher: Wiley
Date: 05-2004
Cerebral Mycobacterium avium infection in an HIV-infected patient following immune reconstitution and cessation of therapy for disseminated Mycobacterium avium complex infection
Publisher: Springer Science and Business Media LLC
Date: 03-04-2001
DOI: 10.1007/PL00011252
Abstract: Reported here is a case of cerebral Mycobacterium avium complex infection that occurred in an HIV-infected patient, who had been treated for disseminated infection and had discontinued clarithromycin and ethambutol following a significant rise in his CD4+ T-cell count after starting highly active antiretroviral therapy. He responded well to excision of the lesion and reinstitution of multidrug therapy. Caution should be exercised when considering ceasing maintenance therapy for disseminated Mycobacterium avium complex infection in HIV-infected patients who demonstrate an apparently good immunologic response to highly active antiretroviral therapy, as this response may not necessarily restore protective immunity against all opportunistic pathogens.
Cell surface markers of regulatory T cells are not associated with increased forkhead box p3 expression in blood CD4+ T cells from HIV-infected patients responding to antiretroviral therapy
Publisher: Wiley
Date: 12-2006
DOI: 10.1111/J.1440-1711.2006.01467.X
Abstract: Regulatory T (Treg) cells may attenuate host immune responses to pathogens, including HIV and opportunistic pathogens in HIV-infected patients. Treated and untreated progressive HIV disease represent a range of immunological scenarios with potentially different roles for Treg cells. A cell surface marker to determine Treg cell numbers would assist in identifying situations where Treg cells are important. Here we show that levels of Foxp3 mRNA are increased in CD4+ T cells from HIV-infected patients responding to antiretroviral therapy. However, the proportion of peripheral blood CD4+ and CD8+ T cells expressing CD25, neuropilin-1, glucocorticoid-induced TNF receptor and lymphocyte activation gene-3 did not differ as a result of treated or untreated HIV infection when compared with HIV-seronegative controls. Hence, none of the putative Treg cell surface markers identified T-cell populations in peripheral blood that mirrored the effects of HIV infection and antiretroviral therapy on Foxp3 expression.
Increased plasma CXCL10 may be a marker of increased risk of immune restoration disease associated with nonviral pathogens
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Chemokine receptor expression on dendritic cells is normal in HIV-infected patients with a stable response to art, but chemokine levels remain elevated
Publisher: Wiley
Date: 12-05-2011
DOI: 10.1002/JMV.22080
Abstract: The development of strategies to optimize T-cell responses in previously immunodeficient HIV patients with a stable virological response to ART requires an understanding of the factors that affect responsiveness. Chemokines direct the migration of dendritic cells (DC) to non-lymphoid tissues infected by secondary pathogens and to lymph nodes where they prime T-cells. Quantitation of mRNA is a sensitive technique enabling assessment of chemokine receptors by CD14⁺ monocytes, myeloid (m)DCs, plasmacytoid (p)DCs, and M-DC8⁺ cells. MDC8⁺ cells invariably expressed less CCR2, CCR5, and CXCR4 than the other cells, but expression of CCR2, CCR5, CCR6, CCR7, CXCR3, and CXCR4 was similar in patients and healthy controls. However plasma levels of CXCL10, CCL5, and CCL2 remained higher in patients than controls. Overall, it appears that chemokine directed migration of DC may not limit immune responses in these patients.
TB-IRIS After Initiation of Antiretroviral Therapy Is Associated With Expansion of Preexistent Th1 Responses Against Mycobacterium tuberculosis Antigens
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
Narrowband UVB phototherapy reduces TNF production by B-cell subsets stimulated via TLR7 from individuals with early multiple sclerosis
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1197
Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies
Publisher: American Society of Hematology
Date: 17-02-2022
DOI: 10.1182/BLOODADVANCES.2021005621
Abstract: Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65) 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities these were manageable and mostly reversible.
Relationship of human immunodeficiency virus viral load in cerebrospinal fluid and plasma in patients co-infected with cryptococcal meningitis
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1093/OFID/OFX032
Abstract: We measured human immunodeficiency virus (HIV) ribonucleic acid (RNA) in paired cerebrospinal fluid (CSF) and plasma s les in a prospective study of 91 HIV-infected, antiretroviral therapy-naive patients with cryptococcal meningitis. Cerebrospinal fluid HIV RNA was lower than in plasma (median 4.7 vs 5.2 log10 copies/mL, P & .0001) and positively correlated with plasma HIV RNA, peripheral CD4+ T-cell percentage, and CSF CXCL10. Plasma/CSF ratio of HIV RNA ranged widely from 0.2 to 265.5 with a median of 2.6. Cerebrospinal fluid quantitative cryptococcal culture positively correlated with CSF CCL2 and CCL3. CSF-plasma viral discordance was not associated with cryptococcal-associated immune reconstitution inflammatory syndrome.
Isotype-switched immunoglobulin G antibodies to HIV Gag proteins may provide alternative or additional immune responses to 'protective' human leukocyte antigen-B alleles in HIV controllers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-02-2013
Syndemic synergy of HPV and other sexually transmitted pathogens in the development of high-grade anal squamous intraepithelial lesions
Publisher: Elsevier BV
Date: 12-2017
Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis
Publisher: Wiley
Date: 07-04-2008
DOI: 10.1111/J.1468-1293.2008.00565.X
Abstract: A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia. Peripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of <100 cells/microL and 17 healthy controls. Leukocytes producing interferon-gamma (IFNgamma) were quantified by enzyme-linked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DR(hi)) and regulatory (CD25 CD127(lo) and CTLA-4(+)) CD4 T-cells were quantified by flow cytometry. Plasma HIV RNA declined and CD4 T-cell counts rose within 8-27 weeks on ART. Mtb IRD patients displayed elevated IFNgamma responses and/or plasma IgG to PPD, but none responded to ESAT-6. Cryptococcal IRD occurred in patients with low baseline CD4 T-cell counts and involved clear IFNgamma and antibody responses to cryptococcal antigen. Proportions of activated and regulatory CD4 T-cells declined on ART, but remained higher in patients than in healthy controls. At the time of IRD, proportions of activated CD4 T-cells and regulatory CD4 T-cells were generally elevated relative to other patients. Cryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFNgamma responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.
Production of IgG2 antibodies to pneumococcal polysaccharides after vaccination of treated HIV patients may be augmented by IL-7Rα signaling in ICOS+ circulating T follicular-helper cells
Publisher: Frontiers Media SA
Date: 24-04-2019
Nadir CD4 T-cell counts continue to influence interferon-gamma responses in HIV patients who began antiretroviral treatment with advanced immunodeficiency
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-03-2014
Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2011
Hepatitis C virus genotype and HIV coinfection affect cytokine mRNA levels in unstimulated PBMC but do not shift the T1/T2 balance
Publisher: Wiley
Date: 08-2006
DOI: 10.1111/J.1440-1711.2006.01451.X
Abstract: Rapid progression of hepatitis C virus (HCV) disease in patients with HIV/HCV may reflect different cytokine responses and be influenced by HCV genotype. This is addressed by a study of patients with HIV/HCV coinfection and infection with HCV genotype 2 or 3 (2/3). They are compared with coinfected patients infected with genotype 1 and HCV monoinfected patients matched for HCV genotype. IFN-gamma, IL-10, IL-4 and IL-4delta2 mRNA were quantified by real-time PCR in unstimulated PBMC and after in vitro stimulation with HCV core or nonstructural 3/4A antigen. In unstimulated PBMC, levels of IFN-gamma and IL-4 mRNA were lowest in HIV/HCV genotype 1 patients, intermediate in HIV/HCV genotype 2/3 patients and highest in HCV genotype 2/3 patients. Neither HCV genotype nor HIV affected levels of IL-10 mRNA in unstimulated PBMC or IFN-gamma, IL-4 and IL-10 mRNA in PBMC stimulated with HCV antigens. Levels of IL-4 and IL-4delta2 mRNA correlated in mitogen-stimulated PBMC from all patient groups but both were low in HIV/HCV genotype 1 patients. Serum soluble CD30 levels (a putative marker of a T2 cytokine environment) did not differ between patient groups. The data do not suggest a shift in the T1/T2 balance driven by HIV coinfection or HCV genotype but either may affect IL-4 bioavailability.
Immunological markers predicting outcome in patients with hepatitis C treated with interferon-α and ribavirin
Publisher: Wiley
Date: 08-2002
DOI: 10.1046/J.1440-1711.2002.01102.X
Abstract: Type 1 (T1) cytokine responses are required for the clearance of hepatitis C virus by cytotoxic T lymphocytes, but can promote liver damage. Interferon-alpha (IFN alpha) can be expected to promote T1 cytokine responses, so treatment outcome may depend on the T1/T2 cytokine environment and levels of immune activation at baseline. This model was tested by monitoring immunological markers in a pilot study of treatment naïve patients given IFN alpha 2b and ribavirin, with the aim of finding markers that predict virological outcome. Soluble (s) CD26/dipeptidyl peptidase IV enzyme activity and levels of sCD30, bioavailable IL-6, sTNF-RI, IL-1ra and nitrite/nitrate (NO(2)(-)/NO(3)(-)) were measured. Levels of IL-1ra and bioavailable IL-6 were lower in patients than controls and did not change with therapy. Treatment decreased sCD26/dipeptidyl peptidase IV enzyme activities and sCD30 levels and increased NO(2)(-)/NO(3)(-) levels. High baseline sCD30 levels predicted an early (P = 0.008) and sustained (P = 0.03) virological response to therapy, suggesting treatment may be more effective in patients with a predominant T2 profile.
Immune restoration disease after antiretroviral therapy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
DOI: 10.1097/01.AIDS.0000131375.21070.06
Abstract: Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For ex le, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.
Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.
Publisher: The American Association of Immunologists
Date: 15-05-2016
Abstract: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.
STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function
Publisher: Rockefeller University Press
Date: 04-05-2015
DOI: 10.1084/JEM.20141992
Abstract: Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that in iduals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic in iduals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
Brief Report:CXCR4 or CCR5 Tropism of Human Immunodeficiency Virus Type 1 Isolates Does Not Determine the Immunological Milieu in Patients Responding to Antiretroviral Therapy
Publisher: Mary Ann Liebert Inc
Date: 12-2006
Abstract: Here we address whether CCR5 or CXCR4 tropism of the predominant viral strain detected before or on combination antiretroviral therapy (ART) explains why some human immunodeficiency virus (HIV)-infected patients who begin ART with advanced HIV disease retain low interferon (IFN)-gamma responses, despite recovery of CD4(+) T cell counts. Tropism was determined by culture and confirmed by gp120 V3 loop sequence of multiple plasma s les in eight adult male patients who began treatment with <50 CD4(+) T cells/microL. Four patients had mixed infections, one had only R5 HIV, and three had only X4 HIV. Of these, two carried CCR5Delta32. Viral tropism was not related to CD4(+) T cell counts or HIV RNA levels. When immunological responses were monitored over several years, IFN-gamma responses to cytomegalovirus were below the median value of uninfected controls and similar in patients with R5, X4, or mixed infection. Interleukin-5 responses were low and plasma soluble CD30 levels were high at treatment onset, but resolved with control of HIV replication irrespective of HIV tropism. Levels of LAG-3 (lymphocyte activation gene-3 protein) were elevated in patients with uncontrolled HIV replication. Hence the immunological milieu did not reflect HIV tropism.
Allogeneic hematopoietic stem cell transplantation recipients have defects of both switched and IgM memory B cells
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BBMT.2008.11.024
Abstract: Allogeneic hematopoietic stem cell transplant (HSCT) recipients were assessed to elucidate memory B cell defects underlying their increased susceptibility to infections, particularly by encapsulated bacteria. Circulating IgM memory B cells (CD19+, CD27+, IgM+) and switched memory B cells (CD19+, CD27+, IgM(-)) were enumerated in allogeneic HSCT recipients (n = 37) and healthy controls (n = 35). T lymphocyte subpopulations and serum levels of immunoglobulins, including IgG subclasses, and antibodies to pneumococcal polysaccharides were also assayed. Allogeneic HSCT recipients were deficient in both switched memory and IgM memory B cells compared to healthy controls (both P < .0001), irrespective of time post-HSCT. Switched memory B cell deficiency correlated with CD4+ T cell deficiency, and both correlated with serum levels of IgG1 (P < .0001), possibly reflecting impaired B cell isotype switching in germinal centres. "Steady-state" serum levels of antibodies to pneumococcal polysaccharides did not correlate with circulating memory B cells. Graft-versus-host disease (GVHD) was associated with lower IgM memory B cell counts and lower serum levels of IgG2, IgG4, IgA, and pneumococcal antibodies. The increased susceptibility of allogeneic HSCT patients to infection may reflect a combination of memory B cell defects, which are most common in patients with a history of GVHD.
Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-02-2015
A rare case of lues maligna with ocular involvement presenting as an unmasking immune reconstitution inflammatory syndrome in a patient with HIV infection
Publisher: Wiley
Date: 24-07-2018
DOI: 10.1111/AJD.12678
Related Organisations
University Of Ioannina School Of Natural Resources And Enterprises Management
Location: Greece
Cluster Of Bioeconomy And Environment Of Western Macedonia, University Of Western Macedonia
Location: Greece
Institute Of Mechanical Engineering, Faculty Of Engineering Of The University Of Porto (IDMEC-FEUP)
Location: Portugal
Related Funding Activities
No related grants have been discovered for Martyn French.