THE INHIBITION OF PRO-APOPTOTIC ICE-LIKE PROTEASES ENHANCES HIV REPLICATION

Accelerated programmed cell death, or apoptosis, contributes to the CD 4(+) T-cell depletion characteristic of infection by human immunodefic iency virus (HIV). It has therefore been proposed that limiting apopto sis may represent a therapeutic modality for HIV infection. We found, however, that T leukemia cells or peripheral blood mononuclear cells ( PBMCs) exposed to HIV-1 underwent enhanced viral replication in the pr esence of the cell death inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fl uoromethylketone (z-VAD-fmk). Furthermore, z-VAD-fmk, which targets th e pro-apoptotic interleukin-1 beta-converting enzyme (ICE)-like protea ses, stimulated endogenous virus production in activated PBMCs derived from HIV-1-infected asymptomatic individuals. These findings suggest that programmed cell death may serve as a beneficial host mechanism to limit HIV spread and that strategies to inhibit it may have deleterio us consequences for the infected host.