TY - JOUR
T1 - HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing
AU - Richard, Jonathan
AU - Sindhu, Sardar
AU - Pham, Tram N.Q.
AU - Belzile, Jean Philippe
AU - Cohen, Éric A.
PY - 2010/2/18
Y1 - 2010/2/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77949903887&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-08-237370
DO - 10.1182/blood-2009-08-237370
M3 - Article
C2 - 20008788
AN - SCOPUS:77949903887
VL - 115
SP - 1354
EP - 1363
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -