Pettit S C, Sanchez R, Smith T, Wehbie R, Derse D, Swanstrom R
Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, 27599, USA.
AIDS Res Hum Retroviruses. 1998 Jul 20;14(11):1007-14. doi: 10.1089/aid.1998.14.1007.
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.
蛋白酶抑制剂是目前对抗人类免疫缺陷病毒1型（HIV-1）最有效的抗病毒药物。在本研究中，我们测定了四种HIV-1蛋白酶抑制剂对人类嗜T淋巴细胞病毒1型（HTLV-I）的作用。用不同浓度的茚地那韦、沙奎那韦、利托那韦或奈非那韦处理感染了HTLV-I的恒河猴细胞。通过这些抑制剂对细胞中病毒Gag蛋白（病毒蛋白酶的天然底物）加工效率的影响来监测其作用效果。这些抑制剂未能阻断HTLV-I Gag的加工过程。为了证实这些发现，将编码HIV-1和HTLV-I感染性拷贝的质粒共转染到人细胞中，随后用这些相同的HIV-1蛋白酶抑制剂处理细胞。在抑制HIV-1复制的IC50的5至50倍浓度之间，HIV-1 Gag裂解受到明显抑制。相比之下，未观察到对HTLV-I Gag加工有影响。在更高浓度下，HIV-1 Gag加工基本完全被抑制，而HTLV-I Gag裂解仍未受影响。因此，这些抑制剂不是HTLV-I Gag加工的有效抑制剂。HIV-1和HTLV-I病毒蛋白酶及加工位点的序列比对表明，与HIV-1蛋白酶相比，HTLV-I蛋白酶的活性位点在底物识别方面可能存在细微差异。
