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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 references36

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          HIV-1 persistence in CD4+ T cells with stem cell-like properties

          Cellular HIV-1 reservoirs that persist despite antiretroviral treatment are incompletely defined. We show that during suppressive antiretroviral therapy, CD4+ T memory stem cells (TSCM) harbor high per-cell levels of HIV-1 DNA, and make increasing contributions to the total viral CD4+ T cell reservoir over time. Moreover, phylogenetic studies suggested long-term persistence of viral quasispecies in CD4+ TSCM cells. Thus, HIV-1 may exploit stem cell characteristics of cellular immune memory to promote long-term viral persistence.
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            Superior T memory stem cell persistence supports long-lived T cell memory.

            Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells.
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              Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys.

              Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV.
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                Author and article information

                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
                : e1004345
                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.

                Article
                PPATHOGENS-D-13-02447
                10.1371/journal.ppat.1004345
                4148445
                25167059
                c2c4358c-9ab2-416c-b61f-f2af008c8212
                Copyright @ 2014

                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.

                History
                : 17 September 2013
                : 16 July 2014
                Page count
                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
                Infectious disease & Microbiology

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