长效HIV进入抑制剂的耐药敏感性和作用机制研究

HIV drugs play an important role in preventing and controlling AIDS currently. It has become a research focus for the development of long-acting HIV entry inhibitors that can block viral fusion with target cell membrane and inhibit viral entry into the host cells by targeting HIV envelope proteins. In this research, we will study the drug sensitivity and related mechanism of a kind of novel long-acting HIV entry inhibitors (PEG- or glycan-modified enfuvirtide). Specifically, we will compare their inhibitory activity on a broad spectrum of HIV-1 isolates predominantly circulating in China, and then determine the effect of the viral envelope protein gene polymorphism on the sensitivity of the viruses to the long-acting HIV entry inhibitors. Through drug stress test, we will analyze the escape mutations of the viruses induced by these long-acting entry inhibitors at different concentrations with different interaction times. Subsequently, we will verify the mutation sites related to the drug-resistance of the viruses to the long-term HIV fusion inhibitors by constructing recombinant viruses and drug resistance phenotype tests. We will reveal the mechanism of the long-acting HIV entry inhibitors by studying the effects of long-acting HIV entry inhibitors on 6-helix bundle and the enfuvirtide resistant strains. Finally, we will use the existing HIV-1 sequences in our laboratory to predict the sensitivity of the HIV-1 isolates predominantly circulating in China to the modified enfuvirtide and other long-acting HIV entry inhibitors, providing the scientific basis for their clinical use.

抗HIV药物是当前预防和治疗艾滋病的主要手段，长效HIV进入抑制剂是以HIV包膜蛋白为靶点，阻断病毒与靶细胞膜融合, 阻止病毒进入细胞的HIV进入抑制剂， 具有更长的半衰期，已成为艾滋病药物的研究热点。本课题在长效化修饰的恩夫韦肽(糖基化和聚乙二醇化恩夫韦肽)的前期研究基础上，针对长效化修饰的恩夫韦肽的耐药敏感性和作用机制问题，通过对我国HIV-1临床病毒株的药物敏感性试验，分析病毒包膜蛋白基因多态性对长效HIV进入抑制剂敏感性的影响；通过药物压力试验，分析不同药物浓度和不同作用时间病毒的变异和逃逸；通过重组病毒的构建研究病毒逃逸对病毒适应性影响；通过药物对gp41六螺旋结构抑制作用以及对恩夫韦肽抗性株的抑制活性，揭示长效HIV进入抑制剂的作用机制。进一步利用本实验室已有HIV基因序列库，预测中国HIV-1流行株对长效HIV进入抑制剂的敏感性，将对今后药物的设计和临床应用具有一定指导意义。

目前尚未研制成功有效的艾滋病疫苗，抗HIV-1药物仍然是治疗艾滋病的主要手段。HIV-1入侵宿主细胞分子机制的逐步阐明，阻止病毒进入细胞的HIV-1融合抑制剂逐渐成为艾滋病药物的研究热点。恩夫韦肽作为目前唯一被美国FDA批准的HIV-1融合抑制剂，因体内半衰期短和注射频繁等缺点严重制约了其临床应用。长效化HIV-1融合抑制剂具有更好的药代动力学特性，不仅可以降低药物的使用频率，减轻患者的痛苦和经济负担，还可以用于预防高危人群HIV-1的感染。PEG化HIV-1融合抑制剂能够有效抑制我国主要流行亚型HIV-1临床分离病毒株的复制，呈现较好的广谱性。PEG化C34通过与NHR结合形成稳定的六螺旋结构抑制病毒包膜蛋白与细胞膜融合并呈现较长的半衰期。PEG40K-NC在大鼠体内的血浆半衰期远远高于C34。进一步使用人/猴嵌合免疫缺陷病毒（SHIV）急性感染的恒河猴模型，研究了PEG40K-NC的体内抗病毒活性，结果表明PEG40K-NC单独给药即可有效抑制SHIV在恒河猴体内的复制（T20单独给药无效）。综上所述，PEG40K-NC显示出良好的药代动力学特性及体内、体外抗HIV活性，并且作用机制明确，可作为新一代长效HIV融合抑制剂进行进一步成药性开发。

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