The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/2/403/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 3, February 2, 1998 403-413

Articles

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

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

From the * Laboratory of Virology and {ddagger} 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 {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.

Address correspondence to Dr. Sandra Gessani, Istituto Superiore di Sanità, Laboratory of Virology, Viale Regina Elena, 299, 00161 Roma, Italy. Phone: 396-49903259; Fax: 396-49902082; E-mail: Gessani{at}virus1.net.iss.it

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


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