Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV⁺ donors by cysteine protease inhibitors

In vitro activation of PBLs from HIV⁺ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV⁺ blood donors, in contrast to only two of 30 control HIV^- donors. CD4⁺ and CD8⁺ T cells from HIV⁺ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV⁺ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV⁺ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV⁺ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.