HIV-1 protease-induced apoptosis
1 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., IOCB & Gilead Research Center, Flemingovo nám. 2, 166 10 Prague, Czech Republic
2 Department of Biochemistry and Microbiology, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic
3 Department of Biotechnology, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic
Retrovirology 2014, 11:37 doi:10.1186/1742-4690-11-37Published: 20 May 2014
Apoptosis is one of the presumptive causes of CD4+ T cell depletion during HIV infection and progression to AIDS. However, the precise role of HIV-1 in this process remains unexplained. HIV-1 protease (PR) has been suggested as a possible factor, but a direct link between HIV-1 PR enzymatic activity and apoptosis has not been established.
Here, we show that expression of active HIV-1 PR induces death in HeLa and HEK-293 cells via the mitochondrial apoptotic pathway. This conclusion is based on in vivo observations of the direct localization of HIV-1 PR in mitochondria, a key player in triggering apoptosis. Moreover, we observed an HIV-1 PR concentration-dependent decrease in mitochondrial membrane potential and the role of HIV-1 PR in activation of caspase 9, PARP cleavage and DNA fragmentation. In addition, in vitro data demonstrated that HIV-1 PR mediates cleavage of mitochondrial proteins Tom22, VDAC and ANT, leading to release of AIF and Hsp60 proteins. By using yeast two-hybrid screening, we also identified a new HIV-1 PR interaction partner, breast carcinoma-associated protein 3 (BCA3). We found that BCA3 accelerates p53 transcriptional activity on the bax promoter, thus elevating the cellular level of pro-apoptotic Bax protein.
In summary, our results describe the involvement of HIV-1 PR in apoptosis, which is caused either by a direct effect of HIV-1 PR on mitochondrial membrane integrity or by its interaction with cellular protein BCA3.