title: Viral protein R upregulates expression of ULBP2 on uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes.
abstract: HIV-1 Vpr triggers NK cell-mediated lysis of infected cells by upregulating ULBP2, a ligand of the NKG2D receptor, through activation of the ATR-mediated DNA damage response. Herein, we demonstrate that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. Indeed, the frequency of uninfected bystander cells expressing high levels of ULBP2 was elevated in a Vpr-dependent manner. Nevertheless, the same does not hold true for a Vpr mutant that is not packaged into virions, suggesting the involvement of virion-associated Vpr in this process. Additionally, we show that soluble Vpr has the ability to induce a DNA damage response and to augment cell-surface ULBP2 upon transducing target cells, including T cells, conditions known to promote NK cell-mediated killing. Overall, these findings suggest that Vpr could contribute to CD4+ T cell loss by rendering uninfected bystander cells susceptible to NK cell-mediated killing.
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.forename: Tram N Q
authors.initials: TN
authors.lastname: Pham
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002460:Cell Line; D004249:DNA Damage; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D015854:Up-Regulation; D014771:Virion / Q000235:genetics / Q000502:physiology; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C423230:ULBP2 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1
keywords: CD4+ T cell depletion; DNA damage response; HIV-1 Vpr; NKG2D ligand; Natural killer cell; ULBP2