Involvement of HIV-1 protease in virus-induced cell killing.
Acute infection of human CD4+ cells with cytopathic strains of HIV-1 causes rapid cell death. The role played by HIV-1 protease (PR) in virus-induced cell killing was investigated by subjecting C8166 cells to a single round of infection. The presence of HIV-1 PR inhibitor saquinavir from 24h post-infection prevented virus-induced cell lysis. This inhibitor caused only a small reduction in the number of infected cells and in the expression of HIV-1-specific proteins. Moreover, treatments that block HIV-1 reinfection, such as AZT or the anti-CD4 antibody leu3.a, exerted little effect on virus-induced cell death. Thus, the specific inhibition of HIV-1 protease reduced the extent of both necrosis and apoptosis in C8166 cells such that most cells survived HIV-1 infection. Continued treatment of the infected cells with saquinavir led to the progressive suppression of HIV-1 expression; no viral proteins being detected 10 days after primary infection. Notably, reactivation of HIV-1 protease in these cells by removing the saquinavir triggered virus replication and cell lysis. These findings may contribute towards a better understanding of HIV-1 pathogenesis, and emphasise the potential of the virus protease as a key therapeutic target in AIDS treatment.
Ventoso
Iván
I
Centro de Biología Molecular Severo Ochoa, Facultad de ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain. iventoso@cnb.uam.es
Navarro
Joaquín
J
Muñoz
Maria A
MA
Carrasco
Luis
L
D017209:Apoptosis / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016333:HIV Protease / Q000187:drug effects / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D019258:Saquinavir / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019258:Saquinavir