Abstract
High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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CD4 Antigens / immunology
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Cells, Cultured
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Cercocebus atys
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Down-Regulation
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Evolution, Molecular
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Gene Products, nef / genetics
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Gene Products, nef / immunology*
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HIV-1 / immunology
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HIV-1 / pathogenicity
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HIV-1 / physiology*
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HIV-2 / immunology
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HIV-2 / physiology
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Humans
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Lentiviruses, Primate / immunology
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Lentiviruses, Primate / physiology*
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / virology
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Lymphocyte Activation
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Molecular Sequence Data
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Phylogeny
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Receptor-CD3 Complex, Antigen, T-Cell / immunology
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Simian Acquired Immunodeficiency Syndrome / immunology
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Simian Immunodeficiency Virus / immunology
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Simian Immunodeficiency Virus / physiology
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T-Lymphocytes / immunology*
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T-Lymphocytes / virology
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nef Gene Products, Human Immunodeficiency Virus
Substances
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CD4 Antigens
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Gene Products, nef
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Receptor-CD3 Complex, Antigen, T-Cell
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nef Gene Products, Human Immunodeficiency Virus
Associated data
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GENBANK/DQ408682
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GENBANK/DQ408683
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GENBANK/DQ408684
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GENBANK/DQ408685
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GENBANK/DQ408686
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GENBANK/DQ408688
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GENBANK/DQ408689
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