Immunosenescent CD57+CD4+ T-cells Accumulate and Contribute to Interferon-γ Responses in HIV Patients Responding Stably to ART (original) (raw)
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AIDS, 2014
Objective-Despite the strong correlation of T-cell CD38 expression with HIV disease progression, evidence linking CD38 expression and dysfunction at the single cell level is scant. Since CD38 + memory CD4 + T cells, especially those from HIV-infected persons, fail to induce CD154 (CD40L) while responding to a superantigen with interferon (IFN)-γ or interleukin (IL)-2, we aimed to determine if recall responses to cytomegalovirus (CMV) were similarly affected in the CD38 + memory CD4 + T-cell subpopulation.
Clinical & Experimental Immunology, 2008
Purified naive and memory CD4 T cells from healthy donors, HIV+ asymptomatic carriers and AtDS patients were examined for their proliferative activity and their pattern of cytokine secretion (IL-4, IL-6, interferon-gamma (IFN-y) and tumour necrosis factor-alpha (TNF-a)) upon stimulation with phytohaemagglutinin (PHA), phorbol myristate acetate (PMA) and cross-linked anti-CD3 MoAb, in the presence of recombinant IL-2 (rIL-2). We found a decrease in the proliferative capacity ofnaive CD4 T cells following stimulation with PHA and PMA, and a sharp decline in this response upon cross-linked anti-CD3 stimulation in both subsets, although it predominated in the naive subpopulation. In AIDS patients, less pronounced impairment of thymidine uptake by the naive subset was found upon PHA and cross-linked anti-CD3 MoAb stimulation. In addition, an altered secretion pattern ofthe different cytokines was observed, consisting of abnormal secretion of IL-6 by both naive and memory cells, an abnormal pattern of IFN-y secretion and frequent loss of detectable lL-4 production by HIV patients. These abnormalities were even more pronounced in AIDS patients than in the asymptomatic carriers. Overall, our results extend previous reports indicating functional impairment of memory CD4 subsets in HIV+ subjects by showing that this impairment involves naive CD4 T cells.
AIDS Research and Treatment, 2012
Objectives. We investigated immune phenotypes of HIV+ patients who present late, considering late presenters (LPs, CD4+ < 350/μL and/or AIDS), advanced HIV disease (AHD, CD4+ < 200/μL and/or AIDS), and AIDS presenters (AIDS-defining condition at presentation, independently from CD4+).Methods. Patients newly diagnosed with HIV at our clinic between 2007–2011 were enrolled. Mann-Whitney/Chi-squared tests and logistic regression were used for statistics.Results. 275 patients were newly diagnosed with HIV between January/2007–March/2011. 130 (47%) were LPs, 79 (29%) showed AHD, and 49 (18%) were AIDS presenters. LP, AHD, and AIDS presenters were older and more frequently heterosexuals. Higher CD8+%, lower CD127+CD4+%, higher CD95+CD8+%, CD38+CD8+%, and CD45R0+CD38+CD8+% characterized LP/AHD/AIDS presentation. In multivariate analysis, older age, heterosexuality, higher CD8+%, and lower CD127+CD4+% were confirmed associated with LP/AHD. Lower CD4+ and higher CD38+CD8+% resulted ind...
Clinical and Vaccine Immunology, 2015
Tuberculosis (TB) remains a global health problem, with vaccination being a necessary strategy for disease containment and elimination. A TB vaccine should be safe and immunogenic as well as efficacious in all affected populations, including HIV-infected individuals. We investigated the induction and maintenance of vaccine-induced memory CD4+T cells following vaccination with the subunit vaccine H1/IC31. H1/IC31 was inoculated twice on study days 0 and 56 among HIV-infected adults with CD4+lymphocyte counts of >350 cells/mm3. Whole venous blood stimulation was conducted with the H1 protein, and memory CD4+T cells were analyzed using intracellular cytokine staining and polychromatic flow cytometry. We identified high responders, intermediate responders, and nonresponders based on detection of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) expressing central (TCM) and effector memory CD4+T cells (TEM) 182 days after the first immunization. A...
Journal of Experimental Medicine, 2003
CD4 ϩ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4 ϩ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4 ϩ T cells were identified in aviremic patients, CD45RA Ϫ CCR7 ϩ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA Ϫ CCR7 Ϫ effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-␥ . In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-␥ . Longitudinal analysis of HIV epitope-specific CD4 ϩ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-␥producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4 ϩ T cell memory depends on IL-2-producing CD4 ϩ T cells and that IFN-␥ only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-␥ only-producing cells that lack self-renewal capacity.
Clinical Immunology, 2008
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-γ 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-γ responses may be affected by numbers and function of circulating DC.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2010
Expression of the activation antigen CD38 on T cells is a strong predictor of the risk of HIV disease progression, but it is not known whether CD38 is a marker or mediator of dysfunction. We examined the relationship between CD38 expression and responses to T-cell receptor stimulation in central memory and effector memory CD4 + T cells in HIV-infected persons and in healthy controls. Basal CD38 expression was preserved by blocking golgi transport with brefeldin A. Intracellular expression of interleukin 2, interferon γ, and CD154 was measured after stimulating peripheral blood mononuclear cells with the superantigen staphylococcal enterotoxin B with or without anti-CD28 costimulation. Interferon-γ responses were comparable or increased in stimulated CD38 + memory cells, and the interleukin 2 responses of costimulated CD38 + central memory cells were decreased in HIV infection. In CD38 + cells and especially in CD38 + cells of HIV-infected persons, stimulated memory cells more often failed to express CD154 (CD40 ligand) when induced to express cytokine. A dissociated cytokine and CD154 expression by memory CD4 T cells may impair interactions between T cells and antigen-presenting cells, contribute to impaired immunity and help explain the relationship between CD38 expression and disease progression in chronic HIV infection.