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 cel l leukemia virus type 1 (HTLV-I). Rhesus monkey cells infected with HT LV-I were treated with different concentrations of indinavir, saquinav ir, ritonavir, or nelfinavir, The effect of these inhibitors was monit ored through their effect on the processing efficiency of the viral Ga g protein in cells, the natural substrate for the viral protease, Thes e inhibitors failed to block processing of HTLV-I Gag, To confirm thes e findings, human cells were cotransfected with plasmids encoding infe ctious copies of HIV-1 and HTLV-I, and the cells were subsequently tre ated with these same HIV-1 protease inhibitors, At concentrations betw een 5 and 50 times the IC50 for inhibition of HIV-1 replication, inhib ition of HIV-1 Gag cleavage was apparent, In contrast, no effect on HT LV-I Gag processing was seen, At higher concentrations, HIV-1 Gag proc essing was essentially completely inhibited whereas HTLV-I Gag cleavag e was still unaffected, Thus, these inhibitors are not effective inhib itors of HTLV-I Gag processing. Sequence alignments of the HIV-1 and H TLV-I viral proteases and processing sites suggest that the active sit e of the HTLV-I protease may have subtle differences in substrate reco gnition compared with the HIV-1 protease.