5th International AIDS Society Conference on HIV Pathogenesis and Treatment Cape Town - July 19 - 22, 2009

HIV-1 Vpr-MEDIATED ATR ACTIVATION AND G2 CELL-CYCLE ARREST INDUCE UP-REGULATION OF NKG2D LIGANDS AND ACTIVATE NK CELL-MEDIATED KILLING

IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOAA201

J. Richard, S. Sindhu, J.-P. Belzile, É.A. Cohen
Institut de Recherches Cliniques de Montréal, Laboratory of Human Retrovirology, Montreal, Canada

BACKGROUND: HIV-1 Vpr activates ATR signaling and promotes G2 cell-cycle arrest by engaging the DDB1-CUL4ADCAF1 E3 ubiquitin ligase. The biological significance of Vpr-mediated G2 arrest in HIV-1 pathogenesis is however not well understood. Interestingly, in the context of cells accumulating DNA damages, ATR activation was shown to upregulate cell-surface NKG2D activating receptor ligands and hence, stimulate NK cell cytotoxic activity. In this study, we examined whether HIV-1 Vpr could enhance expression of NKG2D ligands and modulate NK cell-mediated killing.

METHODS: Cell-surface expression of NKG2D ligands was determined by flow cytometry and susceptibility to NK cellmediated killing was evaluated by chromium release assay.

RESULTS: Expression of Vpr in several human cell lines, including HeLa and CEM NKR T cells, as well as in primary CD4+ T lymphocytes was found to induce an up-regulation of the NKG2D ligands MICB and ULBP2/3. This effect was not observed with Vpr (Q65R), a G2 arrest-defective mutant unable to engage the CUL4A4-DDB1DCAF1 E3 ligase, nor upon treatment of cells with caffeine, a non specific inhibitor of ATR, thus indicating that up-regulation of NKG2D ligands was likely dependent on Vpr-mediated ATR activation and G2 arrest. Importantly, CEM NKR T cells and primary human CD4+ T lymphocytes expressing Vpr, as a transgene or a transduced virion-associated protein, were found to strongly activate NK cell-mediated killing. The role of Vpr in the up-regulation of NKG2D ligands was also investigated in the context of HIV- 1-infected primary CD4+ T cells. Interestingly, we found that up-regulation of ULBP2 induced by HIV-1 infection was further accentuated by Vpr.

2009-07-22
MOAA201
Oral Abstract Session: MOAA2 - Subversion of Immune Responses in HIV Infection

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