A JNK‐dependent pathway is required for HIV‐Vpr‐induced apoptosis in human monocytic cells

Abstract

HIV-1 Vpr causes apoptosis in different kinds of cells including lymphocytes, monocytes, and neuronal cells. Persistently infected monocytic cells serve as a major reservoir of HIV at all stages of disease. It is believed that one of the reasons for monocytes in vivo to be protected from apoptosis is by secretion of different kinds of cytokines in response to HIV infection. C terminal moiety of Vpr is known to cause apoptosis in variety of cell types including monocytes. Herein we have demonstrated that Vpr c terminal peptide (52–96) causes apoptosis in monocytes and monocytic cell lines and the process was caspase dependent. Further, knowing the role of MAPKs in regulation of cell death, we determined the involvement of MAPKs in Vpr induced apoptosis in monocytes. Our results suggest that synthetic Vpr (52–96) and (1–45) peptides induced phosphorylation of all the MAPKs, whereas only Vpr (52–96) peptide induced apoptosis in monocytic cells. The results were confirmed by using JNK stealth RNA. Using a variety of strategies to manipulate JNK activity, we provided evidence that JNK activation is important in mediating Vpr induced apoptosis. Furthermore, Vpr induced apoptosis was mediated by downregulation of antiapoptotic genes Bcl2 and c-IAP1 through activation of upstream JNK MAPK. Understanding the mechanism of apoptosis induced by Vpr will be beneficial for the development of therapeutic approaches.