Catalfamo, M. et al. HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells. Proc. Natl. Acad. Sci. USA 105, 19851-19856

Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2009; 105(50):19851-6. DOI: 10.1073/pnas.0810032105
Source: PubMed


HIV infection is characterized by a brisk immune activation that plays an important role in the CD4 depletion and immune dysfunction of patients with AIDS. The mechanism underlying this activation is poorly understood. In the current study, we tested the hypothesis that this activation is the net product of two distinct pathways: the inflammatory response to HIV infection and the homeostatic response to CD4 T cell depletion. Using ex vivo BrdU incorporation of PBMCs from 284 patients with different stages of HIV infection, we found that CD4 proliferation was better predicted by the combination of CD4 depletion and HIV viral load (R(2) = 0.375, P < 0.001) than by either parameter alone (CD4 T cell counts, R(2) = 0.202, P < 0.001; HIV viremia, R(2) = 0.302, P < 0.001). Interestingly, CD8 T cell proliferation could be predicted by HIV RNA levels alone (R(2) = 0.334, P < 0.001) and this predictive value increased only slightly (R(2) = 0.346, P < 0.001) when CD4 T cell depletion was taken into account. Consistent with the hypothesis that CD4 T cell proliferation is driven by IL-7 as a homeostatic response to CD4 T cell depletion, levels of phosphorylated STAT-5 were found to be elevated in naive subsets of CD4 and CD8 T cells from patients with HIV infection and in the central memory subset of CD4 T cells. Taken together these data demonstrate that at least two different pathways lead to immune activation of T cells in patients with HIV infection and these pathways differentially influence CD4 and CD8 T cell subsets.

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Available from: Michael W Baseler, Feb 11, 2014
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    • "Many efforts have been devoted to better understanding the mechanism governing disease progression and non-progression during HIV infection. Besides the direct cytotoxic effect against CD4+ T cells caused by HIV, immune activation is widely accepted as a good predictor for disease progression [1], [2], [3], [4], [5]. Furthermore, some clinical studies using immunity suppressive drugs to suppress immune activation slowed down the diseases progression [6], [7]. "
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    ABSTRACT: Since statistical relationships between HIV load and CD4+ T cell loss have been demonstrated to be weak, searching for host factors contributing to the pathogenesis of HIV infection becomes a key point for both understanding the disease pathology and developing treatments. We applied Maximum Relevance Minimum Redundancy (mRMR) algorithm to a set of microarray data generated from the CD4+ T cells of viremic non-progressors (VNPs) and rapid progressors (RPs) to identify host factors associated with the different responses to HIV infection. Using mRMR algorithm, 147 gene had been identified. Furthermore, we constructed a weighted molecular interaction network with the existing protein-protein interaction data from STRING database and identified 1331 genes on the shortest-paths among the genes identified with mRMR. Functional analysis shows that the functions relating to apoptosis play important roles during the pathogenesis of HIV infection. These results bring new insights of understanding HIV progression.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Importantly, activation levels of both CD4+ and CD8+ T lymphocytes in HIV infection are strong predictors of disease progression [3,17] and viral control [13], however the causes of this activation are incompletely understood. Moreover, it is likely that the activation of CD4+ and CD8+ lymphocytes are mediated by distinct processes [18,19]. The mechanisms leading to the activation and depletion of CD4+ lymphocytes are of particular interest since their maintenance is critical in staving off the onset of AIDS. "
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    ABSTRACT: Background HIV infection induces chronic immune activation which is associated with accelerated disease progression; the causes of this activation, however, are incompletely understood. We investigated the activation status of CD4+ T cells specific for chronic herpes viruses and the non-persistent antigen tetanus toxoid (TT) in HIV positive and HIV negative donors to assess whether persistent infections contribute to chronic CD4+ T cell activation. Methods Untreated HIV+ patients and healthy, aged matched controls were recruited and activation levels assessed and compared between cells specific for persistent and non-persistent antigens. Activation levels on antigen-specific CD4+ T cells were measured by intracellular cytokine staining following in vitro stimulation with various recall antigens (CMV, EBV, HSV, VZV and TT) in conjunction with cell surface phenotyping. Results Activation levels of herpes virus-specific CD4+ T cell populations, assessed by co-expression of CD38 and HLA-DR, were significantly elevated in HIV+ individuals compared to normal controls and compared to TT-specific responses. In contrast, we found similar levels of activation of TT-specific CD4+ T cells in HIV+ and HIV- donors. Conclusions These results show a disparate distribution of immune activation within CD4+ T cell populations depending on their specificity and suggest that the elevated level of immune activation that characterizes chronic HIV infection may be influenced by the persistence of other antigens.
    Full-text · Article · Feb 2013 · BMC Infectious Diseases
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    • "Besides, PD-1 signalling inhibits T cell effector functions during TB [5] and HIV [22]. The finding of a higher expression of PD-1 on T cells from HIV-TB and HIV-positive individuals support the idea of upregulation of PD-1 by viral proteins, in addition to the enhanced cell activation described for both infections [23,24]. Therefore, higher basal levels of PD-1 on T cells from HIV-TB and HIV-positive subjects may induce dysfunctional M. tuberculosis-specific T cells, reflected in lower levels of IFN-γ production and proliferation in vitro against the antigen. "
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    ABSTRACT: Tuberculosis (TB) continues to be the most frequent cause of illness and death from an infectious agent globally, and its interaction with HIV is having devastating effects. To investigate how HIV alters the immune response to Mycobacterium tuberculosis (Mtb), we assessed basal and Mtb-induced proliferation, cytokine production, and expression of signalling lymphocytic activation molecule (SLAM), inducible costimulator (ICOS) and programmed death-1 (PD-1) on T lymphocytes from HIV-positive individuals coinfected with TB, HIV-positive subjects, TB patients and healthy donors (HD). HIV-TB patients showed increased ICOS, SLAM and PD-1 basal levels on T lymphocytes, whereas HIV-positive individuals displayed elevated levels of SLAM and PD-1, TB patients high levels of SLAM, and HD low levels of the three proteins. Mtb-stimulation enhanced ICOS expression in the four groups, but only TB and HD increased SLAM and PD-1 levels. These data show the immune deregulation that takes place during the immune response against TB in different study populations.
    Full-text · Article · Jun 2012 · Journal of the International AIDS Society
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