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      Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells

      research-article
      1 , 1 ,
      Retrovirology
      BioMed Central
      HIV, Envelope, Akt, p38, CD4 T cell death, CCR5, CD4, Antiviral therapy

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          Abstract

          Background

          The cell surface receptors CD4 and CCR5 bind CCR5-tropic HIV Envelope (Env) glycoprotein during virus attachment. These same receptors have signaling activities related to normal immune cell functions. We also know that Env binds to CCR5 present at high levels on CD4-negative γδ T cells where it signals through p38 MAP kinase to activate caspases and Fas-independent cell death. Here, we asked whether Env signaling through cellular receptors is responsible for death among uninfected CD4+/CCR5+ T cells and what are the effects of Env on CD4+/CCR5-negative cells that might impact HIV infection. The outcomes of Env binding are analyzed in terms of signal transduction and the effects on cell activation or cell death pathways.

          Results

          Env binding to CD4 signals through Erk and Akt kinases. Activation of Erk/Akt suppresses p38 due to CCR5 binding, and allows cell survival. When CD4 signaling was blocked by soluble CD4 or protein kinase inhibitors, p38 activation and Fas-independent cell death were increased among uninfected CD4+ CCR5+ T cells. We also noted specific effects of CD4 signaling on CCR5-negative CD4 T cells in tonsil lymphocyte cultures. Exposure to CCR5-tropic HIV Env (BaL strain) increased expression of CXCR5, PD-1, Fas and FasL. Among CD4+/CCR5- T cells expressing high levels of CXCR5 and PD-1, there were substantial amounts of Fas-dependent cell death. Increased CXCR5 and PD-1 expression was blocked by soluble CD4 or specific inhibitors of the Akt kinase, showing a direct relationship between CD4 signaling, T cell activation and Fas-dependent cell death.

          Conclusions

          Specific inhibition of Akt activation increased Env-dependent cell death of CCR5+ CD4 T cells. The same inhibitor, antibodies blocking the CD4 binding site on gp120, or soluble CD4 also prevented the increase in expression of CXCR5 or PD-1, and reduced the levels of Fas-dependent cell death. The Akt kinase and related signaling events, are key to cell survival that is needed for productive infection, and may be targets for the development of antivirals. Specific inhibitors of Akt would decrease productive infection, by favoring cell death during virus attachment to CD4+ CCR5+ target cells, and reduce immune activation to prevent Fas-dependent death of uninfected CXCR5+ PD-1+ CD4 T cells including T follicular helper cells that share this phenotype.

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          Most cited references36

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          Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

          The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
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            HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease.

            Primary infection with the human immunodeficiency virus (HIV) is generally followed by a burst of viraemia with or without clinical symptoms. This in turn is followed by a prolonged period of clinical latency. During this period there is little, if any, detectable viraemia, the numbers of infected cells in the blood are very low, and it is extremely difficult to demonstrate virus expression in these cells. We have analysed viral burden and levels of virus replication simultaneously in the blood and lymphoid organs of the same individuals at various stages of HIV disease. Here we report that in early-stage disease there is a dichotomy between the levels of viral burden and virus replication in peripheral blood versus lymphoid organs. HIV disease is active in the lymphoid tissue throughout the period of clinical latency, even at times when minimal viral activity is demonstrated in blood.
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              • Article: not found

              Emerging concepts in the immunopathogenesis of AIDS.

              There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.
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                Author and article information

                Contributors
                Journal
                Retrovirology
                Retrovirology
                Retrovirology
                BioMed Central
                1742-4690
                2013
                6 June 2013
                : 10
                : 60
                Affiliations
                [1 ]Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
                Article
                1742-4690-10-60
                10.1186/1742-4690-10-60
                3681682
                23742646
                b005603f-5d3a-4729-a594-e920064d9516
                Copyright ©2013 Li and Pauza; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 February 2013
                : 30 May 2013
                Categories
                Research

                Microbiology & Virology
                hiv,envelope,akt,p38,cd4 t cell death,ccr5,cd4,antiviral therapy
                Microbiology & Virology
                hiv, envelope, akt, p38, cd4 t cell death, ccr5, cd4, antiviral therapy

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