HIV type 1 protease inhibitors fail to inhibit HTLV-I Gag processing in infected cells.
Protease inhibitors are currently the most effective antiviral agents against human immunodeficiency virus type 1 (HIV-1). In this study we determined the effect of four HIV-1 protease inhibitors on human T cell leukemia virus type 1 (HTLV-I). Rhesus monkey cells infected with HTLV-I were treated with different concentrations of indinavir, saquinavir, ritonavir, or nelfinavir. The effect of these inhibitors was monitored through their effect on the processing efficiency of the viral Gag protein in cells, the natural substrate for the viral protease. These inhibitors failed to block processing of HTLV-I Gag. To confirm these findings, human cells were cotransfected with plasmids encoding infectious copies of HIV-1 and HTLV-I, and the cells were subsequently treated with these same HIV-1 protease inhibitors. At concentrations between 5 and 50 times the IC50 for inhibition of HIV-1 replication, inhibition of HIV-1 Gag cleavage was apparent. In contrast, no effect on HTLV-I Gag processing was seen. At higher concentrations, HIV-1 Gag processing was essentially completely inhibited whereas HTLV-I Gag cleavage was still unaffected. Thus, these inhibitors are not effective inhibitors of HTLV-I Gag processing. Sequence alignments of the HIV-1 and HTLV-I viral proteases and processing sites suggest that the active site of the HTLV-I protease may have subtle differences in substrate recognition compared with the HIV-1 protease.
Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, 27599, USA.
S C
SC
Pettit
R
R
Sanchez
T
T
Smith
R
R
Wehbie
D
D
Derse
R
R
Swanstrom
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015683:Gene Products, gag / Q000378:metabolism*; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D014162:Transfection; D014779:Virus Replication
D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D016333:HIV Protease