APOPTOSIS MEDIATED BY HIV PROTEASE IS PRECEDED BY CLEAVAGE OF BCL-2

Expression of the human immunodeficiency virus type 1 (HIV) protease i n cultured cells leads to apoptosis, preceded by cleavage of bcl-2, a key negative regulator of cell death, In contrast, a high level of bcl -2 protects cells in vitro and in vivo from the viral protease and pre vents cell death following HIV infection of human lymphocytes, while r educing the yields of viral structural proteins, infectivity, and tumo r necrosis factor alpha. We present a model for HIV replication in whi ch the viral protease depletes the infected cells of bcl-2, leading to oxidative stress-dependent activation of NF kappa B, a cellular facto r required for HIV transcription, and ultimately to cell death, Purifi ed bcl-2 is cleaved by HIV protease between phenylalanine 112 and alan ine 113. The results suggest a new option for HIV gene therapy; bcl-2 muteins that have noncleavable alterations surrounding the HIV proteas e cleavage site.