Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2

被引:170
作者
Strack, PR [1 ]
Frey, MW [1 ]
Rizzo, CJ [1 ]
Cordova, B [1 ]
George, HJ [1 ]
Meade, R [1 ]
Ho, SP [1 ]
Corman, J [1 ]
Tritch, R [1 ]
Korant, BD [1 ]
机构
[1] DUPONT MERCK PHARMACEUT CO,EXPT STN,DEPT MOL BIOL,WILMINGTON,DE 19880
关键词
AIDS; cell death; NF kappa B; proteolysis;
D O I
10.1073/pnas.93.18.9571
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Expression of the human immunodeficiency virus type 1 (HIV) protease in 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 prevents cell death following HIV infection of human lymphocytes, while reducing the yields of viral structural proteins, infectivity, and tumor necrosis factor alpha. We present a model for HIV replication in which the viral protease depletes the infected cells of bcl-2, leading to oxidative stress-dependent activation of NF kappa B, a cellular factor required for HIV transcription, and ultimately to cell death, Purified bcl-2 is cleaved by HIV protease between phenylalanine 112 and alanine 113. The results suggest a new option for HIV gene therapy; bcl-2 muteins that have noncleavable alterations surrounding the HIV protease cleavage site.
引用
收藏
页码:9571 / 9576
页数:6
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