The HIV-1 vpr R77Q Mutant Induces Apoptosis, G2 Cell Cycle Arrest, and Lower Production of Pro-Inflammatory Cytokines in Human CD4+ T Cells.

Abstract

Acquired immunodeficiency syndrome (AIDS) occurs when HIV depletes CD4+ helper T cells. Some patients develop AIDS slowly or not at all, and are termed long-term non-progressors (LTNP), and while mutations in the HIV-1 Viral Protein R (vpr) gene such as R77Q are associated with LTNP, mechanisms for this correlation are unclear. This study examines the induction of apoptosis, cell cycle arrest, and pro-inflammatory cytokine release in the HUT78 T cell line following infection with replication-competent wild-type strain NL4-3, the R77Q mutant, or a vpr Null mutant. Our results show a significant enhancement of apoptosis and G₂ cell cycle arrest in HUT78 cells infected with R77Q, but not with WT NL4-3 or the vpr Null strain. Conversely, HUT78 cells infected with the WT virus show higher levels of necrosis. We also detected lower TNF and IL-6 release after infection with R77Q vs. WT. The apoptotic phenotype was also seen in the CEM cell line and in primary CD4+ T cells. Protein expression of the R77Q vpr variant was low compared to WT vpr, but expression levels alone cannot explain these phenotypes because the Null virus did not show apoptosis or G₂ arrest. These results suggest that R77Q triggers a non-inflammatory apoptotic pathway that attenuates inflammation, possibly contributing to LTNP.