title: HIV-1 protease-induced apoptosis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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. rumlova@uochb.cas.cz.
authors.forename: Michaela
authors.initials: M
authors.lastname: Rumlová
authors.forename: Ivana
authors.initials: I
authors.lastname: Křížová
authors.forename: Alena
authors.initials: A
authors.lastname: Keprová
authors.forename: Romana
authors.initials: R
authors.lastname: Hadravová
authors.forename: Michal
authors.initials: M
authors.lastname: Doležal
authors.forename: Karolína
authors.initials: K
authors.lastname: Strohalmová
authors.forename: Iva
authors.initials: I
authors.lastname: Pichová
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hájek
authors.forename: Tomáš
authors.initials: T
authors.lastname: Ruml
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D057809:HEK293 Cells; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C471621:AKIP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1