HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing

Jonathan Richard, Sardar Sindhu, Tram N.Q. Pham, Jean Philippe Belzile, Éric A. Cohen

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    93 Citations (Scopus)

    Abstract

    HIV up-regulates cell-surface expression of specific ligands for the activating NKG2D receptor, including ULBP-1, -2, and -3, but not MICA or MICB, in infected cells both in vitro and in vivo. However, the viral factor(s) involved in NKG2D ligand expression still remains undefined. HIV-1 Vpr activates the DNA damage/stress-sensing ATR kinase and promotes G2 cell-cycle arrest, conditions known to up-regulate NKG2D ligands. We report here that HIV-1 selectively induces cell-surface expression of ULBP-2 in primary CD4 + T lymphocytes by a process that is Vpr dependent. Importantly, Vpr enhanced the susceptibility of HIV-1 - infected cells to NK cell - mediated killing. Strikingly, Vpr alone was sufficient to up-regulate expression of all NKG2D ligands and thus promoted efficient NKG2D-dependent NK cell - mediated killing. Delivery of virion-associated Vpr via defective HIV-1 particles induced analogous biologic effects in noninfected target cells, suggesting that Vpr may act similarly beyond infected cells. All these activities relied on Vpr ability to activate the ATR-mediated DNAdamage/stress checkpoint. Overall, these results indicate that Vpr is a key determinant responsible for HIV-1 - induced up-regulation of NKG2D ligands and further suggest an immunomodulatory role for Vpr that may not only contribute to HIV-1 - induced CD4+ T-lymphocyte depletion but may also take part in HIV-1 - induced NK-cell dysfunction.

    Original languageEnglish
    Pages (from-to)1354-1363
    Number of pages10
    JournalBlood
    Volume115
    Issue number7
    DOIs
    Publication statusPublished - 18 Feb 2010

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