Protection against HIV-1 induced apoptosis by inhibition of CPP32beta-related proteases (Meeting abstract).

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Protection against HIV-1 induced apoptosis by inhibition of CPP32beta-related proteases (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 38:A792 1997. Unique Identifier : AIDSLINE MED/97622045
McKenna KA; Dropulic B; Akhtar AJ; Thoburn C; Fuchs EJ; Hess AD; Bedi A; Johns Hopkins Oncology Center, Baltimore, MD 21287

Abstract: Acquired immunodeficiency syndrome (AIDS) involves the depletion of CD4+ T cells through apoptosis mediated by the Fas surface receptor. Because Fas-induced apoptosis requires activation of the CPP32beta protease, we studied its role in HIV-induced apoptosis. We examined the effect of the HIV-1 Tat protein on apoptosis of Jurkat T cells and human peripheral blood mononuclear cells (PBMCs) induced by ligation of T-cell receptor TCR; by anti-CD3) or the CD4 receptor (by HIV-1 gp120 and anti gp120). Tat sensitized Jurkat cells and PBMCs to CD3- or gp120-induced apoptosis. Since Tat upregulates Fas ligand (FasL) expression, we tested the requirement of Fas-FasL in CD3-induced apoptosis of T cells from wild-type mice (wt) and Fas-deficient lpr mice. Unlike T cells from wt mice, T cells from lpr mice were resistant to activation-induced apoptosis. Exposure of CD3-activated T cells (ATCs) to Tat resulted in proteolytic cleavage and activation of CPP32beta. Tat-mediated apoptosis of ATCs was inhibited by Ac-DEVD-CHO, a specific inhibitor of CPP32beta. Ac-DEVD-CHO also prevented apoptosis of CD4+ ATCs in response to gp120 and polyclonal anti-gp120. Most importantly, Ac-DEVD-CHO protected ATCs from apoptosis resulting from direct HIV-1 infection of Jurkat cells in vitro. These data suggest that HIV-1 mediated apoptosis is transduced through Fas/FasL and that inhibition of CPP32beta may be a therapeutically attractive approach to prevent CD4+ T cell depletion in AIDS.

Keywords: *Apoptosis *Gene Products, tat/PHARMACOLOGY *HIV Infections/PATHOLOGY *HIV-1 *Peptide Peptidohydrolases/PHARMACOLOGY
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