Abstract
Tetherin is an IFN-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. HIV-1 overcomes this restriction factor by expressing HIV-1 viral protein U (Vpu), which down-regulates and degrades tetherin. We report that mutations in Vpu that impair tetherin antagonism increase the susceptibility of HIV-infected cells to antibody-dependent cell-mediated cytotoxicity (ADCC), and conversely that RNAi knockdown of tetherin, but not other cellular proteins down-modulated by Vpu, decreases the susceptibility of HIV-infected cells to ADCC. These results reveal that Vpu protects HIV-infected cells from ADCC as a function of its ability to counteract tetherin. By serving as link between innate and adaptive immunity, the antiviral activity of tetherin may be augmented by virus-specific antibodies, and hence much greater than previously appreciated.
Keywords:
AIDS; BST-2; CD317; lentivirus.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Substitution
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Antibody-Dependent Cell Cytotoxicity / drug effects
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Antibody-Dependent Cell Cytotoxicity / immunology*
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Antigens, CD / metabolism
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CD4 Antigens / metabolism
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Cytoprotection* / drug effects
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GPI-Linked Proteins / antagonists & inhibitors
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GPI-Linked Proteins / metabolism
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Gene Deletion
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HIV Infections / immunology*
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HIV Infections / pathology*
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Human Immunodeficiency Virus Proteins / metabolism*
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Humans
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Interferon-alpha / pharmacology
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RNA Interference / drug effects
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Receptors, Cell Surface / metabolism
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Signaling Lymphocytic Activation Molecule Family Member 1
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Viral Regulatory and Accessory Proteins / metabolism*
Substances
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Antigens, CD
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BST2 protein, human
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CD4 Antigens
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GPI-Linked Proteins
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Human Immunodeficiency Virus Proteins
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Interferon-alpha
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Receptors, Cell Surface
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Viral Regulatory and Accessory Proteins
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vpu protein, Human immunodeficiency virus 1
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Signaling Lymphocytic Activation Molecule Family Member 1