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      Eradication of HIV-1 from the Macrophage Reservoir: An Uncertain Goal?

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          Abstract

          Human immunodeficiency virus type 1 (HIV-1) establishes latency in resting memory CD4+ T cells and cells of myeloid lineage. In contrast to the T cells, cells of myeloid lineage are resistant to the HIV-1 induced cytopathic effect. Cells of myeloid lineage including macrophages are present in anatomical sanctuaries making them a difficult drug target. In addition, the long life span of macrophages as compared to the CD4+ T cells make them important viral reservoirs in infected individuals especially in the late stage of viral infection where CD4+ T cells are largely depleted. In the past decade, HIV-1 persistence in resting CD4+ T cells has gained considerable attention. It is currently believed that rebound viremia following cessation of combination anti-retroviral therapy (cART) originates from this source. However, the clinical relevance of this reservoir has been questioned. It is suggested that the resting CD4+ T cells are only one source of residual viremia and other viral reservoirs such as tissue macrophages should be seriously considered. In the present review we will discuss how macrophages contribute to the development of long-lived latent reservoirs and how macrophages can be used as a therapeutic target in eradicating latent reservoir.

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          Most cited references124

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          Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

          Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.
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            The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein.

            The HIV-1 accessory protein Vpu counteracts a host factor that restricts virion release from infected cells. Here we show that the interferon-induced cellular protein BST-2/HM1.24/CD317 is such a factor. BST-2 is downregulated from the cell surface by Vpu, and BST-2 is specifically expressed in cells that support the vpu phenotype. Exogenous expression of BST-2 inhibits HIV-1 virion release, while suppression of BST-2 relieves the requirement for Vpu. Downregulation of BST-2 requires both the transmembrane/ion channel domain and conserved serines in the cytoplasmic domain of Vpu. Endogenous BST-2 colocalizes with the HIV-1 structural protein Gag in endosomes and at the plasma membrane, suggesting that BST-2 traps virions within and on infected cells. The unusual structure of BST-2, which includes a transmembrane domain and a lumenal GPI anchor, may allow it to retain nascent enveloped virions on cellular membranes, providing a mechanism of viral restriction counteracted by a specific viral accessory protein.
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              HIV infection: epidemiology, pathogenesis, treatment, and prevention.

              HIV prevalence is increasing worldwide because people on antiretroviral therapy are living longer, although new infections decreased from 3.3 million in 2002, to 2.3 million in 2012. Global AIDS-related deaths peaked at 2.3 million in 2005, and decreased to 1.6 million by 2012. An estimated 9.7 million people in low-income and middle-income countries had started antiretroviral therapy by 2012. New insights into the mechanisms of latent infection and the importance of reservoirs of infection might eventually lead to a cure. The role of immune activation in the pathogenesis of non-AIDS clinical events (major causes of morbidity and mortality in people on antiretroviral therapy) is receiving increased recognition. Breakthroughs in the prevention of HIV important to public health include male medical circumcision, antiretrovirals to prevent mother-to-child transmission, antiretroviral therapy in people with HIV to prevent transmission, and antiretrovirals for pre-exposure prophylaxis. Research into other prevention interventions, notably vaccines and vaginal microbicides, is in progress. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                31 March 2015
                April 2015
                : 7
                : 4
                : 1578-1598
                Affiliations
                [1 ]Department of Biology, SBA School of Science and Engineering, Lahore University of Management Sciences, Lahore 54792, Pakistan; E-Mails: wazim_cemb@ 123456hotmail.com (W.A.); m.tariq@ 123456lums.edu.pk (M.T.)
                [2 ]Laboratory of Drug Discovery and Structural Biology, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad 38000, Pakistan; E-Mail: hamzamgondal@ 123456gmail.com
                [3 ]Department of Virology, University of Franche-Comté, CHRU Besançon, UPRES EA4266 Pathogens and Inflammation, SFR FED 4234, 25030 Besançon, France; E-Mail: amit.aiims2005@ 123456gmail.com
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: georges.herbein@ 123456univ-fcomte.fr ; Tel.: +33-381-21-88-77; Fax: +33-381-66-56-95.
                Article
                viruses-07-01578
                10.3390/v7041578
                4411666
                25835530
                3025f05a-a6cb-45e3-9e2e-6ab96136b912
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 February 2015
                : 24 March 2015
                Categories
                Review

                Microbiology & Virology
                hiv-1,cart,latency,reservoirs,macrophage
                Microbiology & Virology
                hiv-1, cart, latency, reservoirs, macrophage

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