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Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals

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      Abstract

      A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated (“putative progressors”, PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (T SCM ( p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = −0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (T CM) cells ( p = 0.035), and the total number of T CM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ T CM and T SCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.

      Author Summary

      Here we assessed correlates of protection from disease progression in a rare subset of HIV-infected individuals, viremic non-progressors (VNP). These individuals have high viral load for several years. In contrast to the majority of infected individuals, however, these individuals do not progress to AIDS. Here we found this lack of progression was associated with selective preservation of two critical subsets of memory CD4+ T cells, central memory (T CM) and stem-cell memory (T SCM) cells. Compared to HIV-infected putative progressors, VNPs had higher proliferation of these indispensable subsets of memory cells. In addition, the long-lived CD4+ T CM and T SCM cells in VNPs had decreased HIV infection compared to the less critical effector memory CD4+ T cells, which indicates a possible mechanism by which VNPs maintain their CD4+ T cell pool after several years of infection, and remain free from AIDS progression.

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      Most cited references 45

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      Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.

      Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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        HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation.

        HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.
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          Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage.

          To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4+ T cells fell to
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            Author and article information

            Affiliations
            [1 ]Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America
            [2 ]Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America
            [3 ]Yerkes Primate Research Center, Emory Vaccine Center and Department of Pathology, Emory University, Atlanta, Georgia, United States of America
            [4 ]Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
            [5 ]Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
            [6 ]Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America
            [7 ]Institute for Immunology, University of California Irvine, Irvine, California, United States of America
            [8 ]Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy
            [9 ]Division of Infectious Diseases, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, United States of America
            Vaccine Research Center, National Institutes of Health, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: NRK MML BJ DC CT MPa JMB FK PWH GS. Performed the experiments: NRK SEB AH JT LERS JPG. Analyzed the data: NRK SEB AH MPe MPa LERS JPG NP. Contributed reagents/materials/analysis tools: MML BJ DC CT JNM SGD ES FMH FK. Wrote the paper: NRK SEB AH FK PWH GS.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            August 2014
            28 August 2014
            : 10
            : 8
            25167059 4148445 PPATHOGENS-D-13-02447 10.1371/journal.ppat.1004345

            This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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            Pages: 13
            Funding
            This work was supported by: the Hector Foundation and the Deutsche Forschungsgemeinschaft (Leibniz award to FK), and NIH/NIAID grants P01 AI 076174 (Cleveland Immunopathogensis Program), R01 AI110334 (MPa), K22 AI098440 (NRK) and in part by University of Washington Center for AIDS Research, P30 AI027757 and University of California San Francisco Center for AIDS Research, P30 AI027763 and R24 AI067039. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Immune Cells
            Immunology
            Clinical Immunology
            Microbiology
            Medical Microbiology
            Microbial Pathogens
            Viral Pathogens
            Immunodeficiency Viruses
            HIV
            Medicine and health sciences
            Diagnostic medicine
            HIV clinical manifestations
            Infectious Diseases
            Viral Diseases

            Infectious disease & Microbiology

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