HIV-1 Vpu Downmodulates ICAM-1 Expression, Resulting in Decreased Killing of Infected CD4+T Cells by NK Cells.
HIV-1 Vpu is known to alter the expression of numerous cell surface molecules. Given the ever-increasing list of Vpu targets identified to date, we undertook a proteomic screen to discover novel cell membrane proteins modulated by this viral protein. Plasma membrane proteome isolates from Vpu-inducible T cells were subjected tostable isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry analysis, and putative targets were validated by infection of primary CD4+T cells. We report here that while intercellular adhesion molecule 1 (ICAM-1) and ICAM-3 are upregulated by HIV-1 infection, expression of Vpu offsets this increase by downregulating these molecules from the cell surface. Specifically, we show that Vpu is sufficient to downregulate and deplete ICAM-1 in a manner requiring the Vpu transmembrane domain and a dual-serine (S52/S56) motif necessary for recruitment of the beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) component of the Skp, Cullin, F-box (SCFβ-TrCP) E3 ubiquitin ligase. Vpu interacts with ICAM-1 to induce its proteasomal degradation. Interestingly, the E3 ubiquitin ligase component β-TrCP-1 is dispensable for ICAM-1 surface downregulation yet is necessary for ICAM-1 degradation. Functionally, Vpu-mediated ICAM-1 downregulation lowers packaging of this adhesion molecule into virions, resulting in decreased infectivity. Importantly, while Vpu-mediated downregulation of ICAM-3 has a limited effect on the conjugation of NK cells to HIV-1-infected CD4+T cells, downregulation of ICAM-1 by Vpu results in a reduced ability of NK cells to bind and kill infected T cells. Vpu-mediated ICAM-1 downregulation may therefore represent an evolutionary compromise in viral fitness by impeding the formation of cell-to-cell contacts between immune cells and infected T cells at the cost of decreased virion infectivity.IMPORTANCEThe major barrier to eradicating HIV-1 infection is the establishment of treatment-resistant reservoirs early in infection. Vpu-mediated ICAM-1 downregulation may contribute to the evasion of cell-mediated immunity during acute infection to promote viral dissemination and the development of viral reservoirs. By aiding the immune system to clear infection prior to the development of reservoirs, novel treatments designed to disrupt Vpu-mediated ICAM-1 downregulation may be beneficial during acute infection or as a prophylactic treatment.
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
Scott M
SM
Sugden
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada.
Tram N Q
TNQ
Pham
Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada eric.cohen@ircm.qc.ca.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Québec, Canada.
Éric A
ÉA
Cohen
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D015536:Down-Regulation; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D025941:Protein Interaction Mapping; D059748:Proteolysis; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins
D054298:Human Immunodeficiency Virus Proteins; D018799:Intercellular Adhesion Molecule-1; D054334:Viral Regulatory and Accessory Proteins; C573420:ICAM1 protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
ICAM-1; NK cell-mediated killing; Vpu; human immunodeficiency virus; immune evasion; immunological synapse; viral infectivity