HIV包膜蛋白gp120降解多肽形成淀粉样纤维结构促进HIV感染的研究

Recent findings showed that peptides released by physiological cleavage of semen coagulum proteins and prostatic acid phosphatase formed amyloid fibrils that could enhance HIV-1 infection by several orders of magnitude. Our previous studies also found HIV-1 gp120 derived peptides could spontaneously form amyloid fibrils that drastically enhanced HIV-1 infection. These peptidic viral infection enhancers could counteract the anti-viral efficacy of many anti-HIV drugs. Then, in the body of HIV positive patients, whether gp120 would degrade to peptides which can form amyloid fibrils and enhance the HIV infection? Whether the in vivo degradation of HIV gp120 is a contributing factor to the onset of AIDS? Is this one of the mechanisms of anti-HIV drug resistance? In the present project, firstly we tried to confirm the virus enhancement effect and the mechanism of gp120 derived peptides. In the meantime, we want to study the blood hydrolysis and intracellular degradation process of HIV gp120 protein. Also, whether the degraded peptides form amyloid structure or not was detected, as well as whether they can enhance HIV infection and reduce the activities of anti-HIV drugs. The purpose of this project is to elaborate the mechanism of virus infection enhancement effect of HIV gp120 degradation peptides and its role in the onset of AIDS. A new kind of drug target for HIV prevention and treatment is expeced.

近年来发现精液中前列腺酸性磷酸酶、生精蛋白的一些降解多肽，在形成淀粉样纤维之后，可以成百倍地增强HIV的感染。我们此前也发现衍生于病毒包膜蛋白gp120的多肽，能自发形成淀粉样纤维结构，显著促进HIV的感染。这些病毒感染增强多肽还可进一步降低艾滋病防治药物的抗HIV活性。那么，在HIV感染者体内的gp120是否会降解成这样能形成淀粉样纤维结构的多肽，促进HIV的感染呢？HIV gp120在体内的降解是否是艾滋病发病的促进因素？是否是抗艾滋病药物产生耐药的机制之一呢？本项目拟进一步确认gp120衍生多肽促进HIV感染的作用和机制，同时研究gp120蛋白在血液中和细胞内降解的过程，并检测降解的多肽是否形成淀粉样结构，促进HIV的感染，降低抗艾滋病药物的活性。本课题旨在阐述HIV gp120降解多肽促进HIV感染的分子机制，探讨其在艾滋病发病和药物防治中的作用，期望发现药物干预的新靶点。

淀粉样纤维是人类很多疾病的致病因子，近年来研究发现精液中存在淀粉样纤维能显著地增强HIV的感染。我们此前也发现衍生于病毒包膜蛋白gp120的多肽，能自发形成淀粉样纤维结构，显著促进HIV的感染。这些病毒感染增强多肽还可进一步降低艾滋病防治药物的抗HIV活性。那么，在HIV感染者体内的gp120是否会降解成这样能形成淀粉样纤维结构的多肽，促进HIV的感染呢？HIV gp120在体内的降解是否是艾滋病发病的促进因素？是否是抗艾滋病药物产生耐药的机制之一呢？本项目通过多肽学方法、体外酶解实验、病毒感染实验、病人临床淋巴漏液和淋巴组织切片，发现艾滋病人淋巴组织中存在着HIV-1 gp120来源的淀粉样纤维，这类纤维不仅促进病毒感染，加速疾病进程，而且拮抵抗逆转录病毒治疗的疗效，加大艾滋病治愈的难度并可能是病毒耐药的新机制，提示病毒来源的淀粉样纤维是艾滋病治疗的潜在新靶点。