HIV蛋白酶抑制剂是抗逆转录病毒治疗中贡献最大的组成部分。近来研究发现，HIV蛋白酶抑制剂除了抑制HIV蛋白酶，还意外地在HIV的细胞穿入环节抑制病毒，即存在其他的药物作用靶点。申请人前期研究证明了HIV蛋白酶抑制剂可与HIV包膜蛋白的gp41胞质尾区结合，并初步鉴定了结合位点；结合抑制剂后，gp41介导的膜融合功能受阻。本研究拟进一步验证HIV蛋白酶抑制剂与gp41胞质尾区结合的关键位点；研究HIV蛋白酶抑制剂对病毒与宿主细胞膜融合的抑制效果；并使用荧光蛋白技术，从包膜蛋白构象变化角度，进一步研究HIV蛋白酶抑制剂阻碍病毒与靶细胞膜融合的机制。研究成果可为HIV蛋白酶抑制剂类药物的应用和艾滋病临床治疗提供新思路。

HIV protease inhibitor is a major contributor of antiretroviral therapies. According to the latest finding, HIV protease inhibitors not only block the activity of HIV protease, but also unexpectedly hinder the HIV fusion with host cells, which indicates that there are other target sites for HIV protease inhibitors. The applicant has proved that HIV protease inhibitors can bind to gp41 cytoplasmic tail region, tentatively identified the binding site of HIV protease inhibitors, and demonstrated that inhibitor binding prevented the function of gp41 in membrane fusion. This grant proposal is aimed at verifying the HIV protease inhibitor targeting residues at the gp41 cytoplasmic tail, studying the inhibitory efficacy of HIV protease inhibitors on the membrane fusion between viruses and host cells, and exploring the mechanism of inhibition based on the conformational change of gp41. The outcome of this project could promote the novel clinical application of HIV protease inhibitor usage and AIDS treatments.