HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing
Article [Accepted Manuscript]
- Institut de recherches cliniques de Montréal
- Faculté de médecine - Département de microbiologie, infectiologie et immunologie
HIV upregulates cell-surface expression of specific ligands for the activating NKG2D receptor, including ULBP-1, -2, -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 upregulate 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 upregulate 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 biological effects in non-infected target cells, suggesting that Vpr may act similarly beyond infected cells. All these activities relied on Vpr ability to activate the ATR-mediated DNA damage/stress checkpoint. Overall, these results indicate that Vpr is a key determinant responsible for HIV-1-induced upregulation 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.
Richard, J., Sindhu, S., Pham, T.N.Q., Belzile, J.-P., Cohen, É.A. "HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing". Blood, 115(7): 1354-1363, 2010.