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L. Conti^*, G. Rainaldi, P. Matarrese, B. Varano^*, R. Rivabene, S. Columba^*, A. Sato, F. Belardelli^*, W. Malorni, and S. Gessani^*

From the ^* Laboratory of Virology and Ultrastructures, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy; and Shionogi Institute for Medical Science, Mishima Settsu-shi, Osaka 566, Japan

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 (TNF-), 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- 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.

¹ Abbreviations used in this paper: CHX, cycloheximide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mRNA, messenger RNA; PI, propidium iodide.

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