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 somehow appear to be protected from apoptosis, which generally occurs in bystander cells. Vpr is an auxiliary HIV-1 protein, which, unlike the other regulatory gene products, is present at high copy number in virus particles. We established stable transfectants of CD4+ T Jurkat cells constitutively expressing low levels of vpr. These clones exhibited cell cycle characteristics similar to those of control-transfected cells. Treatment of control clones with apoptotic stimuli (i.e., cycloheximide/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 protection 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 the control clones. Moreover, the constitutive expression of HIV-1 vpr resulted in the upregulation of bcl-2, an oncogene endowed with antiapoptotic activities, and in the downmodulation of bax, a proapoptotic factor of the bcl-2 family. Altogether, these results suggest that low levels of the endogenous vpr protein can interfere with the physiological turnover of T lymphocytes at early stages of virus infection, thus facilitating HIV persistence and, subsequently, viral spread. This might explain why apoptosis mostly occurs in bystander uninfected cells in AIDS patients.

Characterization of the response of growth and differentiation to lipoproteins and agents affecting cholesterol metabolism in murine neuroblastoma cells.

Treatment with mevinolin, a competitive inhibitor of HMGCoAR, the key enzyme of isoprenoid metabolism, causes the arrest of proliferation and the differentiation of a neuroblastoma cell line (N18TG2). Mevalonate and high density lipoproteins partially restore growth. Cholesterol synthesis in the presence of mevinolin remains active, because in these cells the key enzyme HMG-CoA reductase is not completely inhibited by this drug. The fact that cell growth is reduced, while cholesterogenesis remains active, suggests that mevinolin acts by interfering with the synthesis of some unknown compound, other than cholesterol, which is necessary for proliferation.