THE HIV-1 VPR PROTEIN ACTS AS A NEGATIVE REGULATOR OF APOPTOSIS IN A HUMAN LYMPHOBLASTOID T-CELL LINE - POSSIBLE IMPLICATIONS FOR THE PATHOGENESIS OF AIDS

Although apoptosis is considered one of the major mechanisms of CD4(+) T cell depletion in HIV-infected patients, the virus-infected cells s omehow appear to be protected from apoptosis, which generally occurs i n bystander cells. Vpr is an auxiliary HIV-1 protein, which, unlike th e other regulatory gene products, is present at high copy number in vi rus particles. We established stable transfectants of CD4(+) T Jurkat cells constitutively expressing low levels of vpr. These clones exhibi ted cell cycle characteristics similar to those of control-transfected cells. Treatment of control clones with apoptotic stimuli (i.e., cycl oheximide/tumor necrosis factor alpha (TNF-alpha), anti-Fas antibody, or serum starvation) resulted in a massive cell death by apoptosis. In contrast, all the vpr-expressing clones showed an impressive protecti on from apoptosis independently of the inducer. Notably, vpr antisense phosphorothioate oligodeoxynucleotides render vpr-expressing cells as susceptible to apoptosis induced by cycloheximide and TNF-alpha as th e control clones. Moreover, the constitutive expression of HIV-1 vpr r esulted in the upregulation of bcl-2, an oncogene endowed with antiapo ptotic activities, and in the downmodulation of bax, a proapoptotic fa ctor of the bcl-2 family. Altogether, these results suggest that low l evels of the endogenous vpr protein can interfere with the physiologic al turnover of T lymphocytes at early stages of virus infection, thus facilitating HIV persistence and, subsequently, viral spread. This mig ht explain why apoptosis mostly occurs in bystander uninfected cells i n AIDS patients.