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      HIV–1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent Cellular Reservoirs

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          Abstract

          HIV causes a chronic infection characterized by depletion of CD4 + T lymphocytes and development of opportunistic infections. Despite drugs that inhibit viral spread, HIV has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy and the immune response. Here we used CD34 + cells from infected people as well as in vitro studies of wild type HIV to demonstrate infection and killing of CD34 + multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A novel reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have important implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

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          Most cited references16

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          Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery.

          In vivo transduction of nondividing cells by human immunodeficiency virus type 1 (HIV-1)-based vectors results in transgene expression that is stable over several months. However, the use of HIV-1 vectors raises concerns about their safety. Here we describe a self-inactivating HIV-1 vector with a 400-nucleotide deletion in the 3' long terminal repeat (LTR). The deletion, which includes the TATA box, abolished the LTR promoter activity but did not affect vector titers or transgene expression in vitro. The self-inactivating vector transduced neurons in vivo as efficiently as a vector with full-length LTRs. The inactivation design achieved in this work improves significantly the biosafety of HIV-derived vectors, as it reduces the likelihood that replication-competent retroviruses will originate in the vector producer and target cells, and hampers recombination with wild-type HIV in an infected host. Moreover, it improves the potential performance of the vector by removing LTR sequences previously associated with transcriptional interference and suppression in vivo and by allowing the construction of more-stringent tissue-specific or regulatable vectors.
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            HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes.

            Cytotoxic T lymphocytes (CTLs) lyse virally infected cells that display viral peptide epitopes in association with major histocompatibility complex (MHC) class I molecules on the cell surface. However, despite a strong CTL response directed against viral epitopes, untreated people infected with the human immunodeficiency virus (HIV-1) develop AIDS. To resolve this enigma, we have examined the ability of CTLs to recognize and kill infected primary T lymphocytes. We found that CTLs inefficiently lysed primary cells infected with HIV-1 if the viral nef gene product was expressed. Resistance of infected cells to CTL killing correlated with nef-mediated downregulation of MHC class I and could be overcome by adding an excess of the relevant HIV-1 epitope as soluble peptide. Thus, Nef protected infected cells by reducing the epitope density on their surface. This effect of nef may allow evasion of CTL lysis by HIV-1-infected cells.
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              Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein.

              Like other pathogenic viruses, HIV-1 down-modulates surface expression of major histocompatibility complex class I (MHC-I) molecules in infected cells, thus impairing lysis by cytotoxic T lymphocytes. We have observed that this phenomenon depends on the expression of Nef. nef is an early gene of primate lentiviruses, which is necessary for maintaining high virus loads and inducing AIDS. Nef is not necessary for viral replication in vitro and stimulates the endocytosis of CD4. We show that the expression of MHC-I at the surface of lymphoid, monocytic and epithelial cells was reduced in the presence of Nef protein from various HIV-1 strains. Whereas MHC-I protein synthesis and transport through the endoplasmic reticulum and cis Golgi apparatus occurred normally in Nef(+) cells, surface MHC-I molecules were rapidly internalized, accumulated in endosomal vesicles and were degraded. The stimulation of MHC-I endocytosis by Nef represents a previously undocumented viral mechanism for evading the immune response.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nature medicine
                1078-8956
                1546-170X
                19 March 2010
                7 March 2010
                April 2010
                1 October 2010
                : 16
                : 4
                : 446-451
                Affiliations
                [1 ]Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109 USA
                [2 ]Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109 USA
                [3 ]Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 USA
                [4 ]Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109 USA
                [5 ]Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109 USA
                Author notes
                [†]

                Corresponding author: Phone: 734 615-1320, Fax: 734 -615-5252, klcollin@ 123456umich.edu

                [*]

                current address: Division of Hematology, Blood & Bone Marrow Transplantation, San Antonio Military Medical Center, Department of Internal Medicine, University of Texas Health Science Center, San Antonio, TX 78236

                [**]

                These authors contributed equally

                Article
                nihpa175238
                10.1038/nm.2109
                2892382
                20208541
                4714f28a-10d4-4365-b877-a1825b91e652

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI051192-07 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI051192-06S1 ||AI
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                Medicine
                Medicine

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