Role of Natural Pseudotyping with Other Viruses in HIV Transmission

描述 摘要： 尽管在了解艾滋病毒-1发病机制和开发强大的抗病毒药物方面取得了重大进展，但全球艾滋病大流行仍在继续扩大。HIV-1主要通过性接触传播，目前全球有3000多万人感染。在世界一些地区，如南部非洲，艾滋病毒-1感染率超过20%。艾滋病毒-1在这些国家的年轻女性中的毁灭性传播似乎与感染的总体风险不成比例。因此，有可能是生物辅助因素促成了病毒的传播。这一建议的假设是，HIV-1在我们称为“自然伪分型”的过程中获得伽玛逆转录病毒(小鼠白血病病毒相关病毒)的包膜糖蛋白，扩大了HIV-1的细胞嗜性，使其能够直接感染阴道上皮细胞，从而显著增加了性交中感染的风险。我们提出了一个由四个主要目标组成的分子流行病学研究。1)完成伽玛逆转录病毒/HIV-1假分型的体外研究；2)证明当地捐赠者中伽马逆转录病毒/HIV-1混合感染；3)在动物模型中证明伽玛逆转录病毒假分型对阴道传播的影响；4)确定南部非洲伽玛逆转录病毒感染和HIV-1联合感染的流行率。HIV-1的自然伪分型预计会发生在同时感染HIV-1和伽马逆转录病毒(XMRV/MLV)的人身上，因为这两种病毒的细胞嗜性重叠，包括T细胞。在血液或淋巴组织中形成XMRV伪型HIV-1(HIV-1/gp70)(现在具有XMRV的细胞嗜性)将导致HIV-1感染正常耐药的泌尿生殖道细胞。这些细胞在感染XMRV之前或之后会导致HIV-1/gp70释放到精液或阴道分泌物中。HIV-1自然伪分型的潜在影响是深远的。

DESCRIPTION Abstract: The global AIDS pandemic continues to expand despite significant advances in understanding HIV-1 pathogenesis and the development of powerful antiviral drugs. HIV-1 is transmitted primarily through sexual contact and more than 30 million people are currently infected worldwide. In some regions of the world such as southern Africa the prevalence of HIV-1 infection exceeds 20%. The devastating spread of HIV-1 in young women in these countries appears out of proportion to the overall risk of infection. Thus it is possible that a biological co-factor contributes to virus spread. The hypothesis of this proposal is that acquisition by HIV- 1 of the envelope glycoprotein of gammaretroviruses (murine leukemia virus-related viruses) in a process we call ""natural pseudotyping"" expands the cellular tropism of HIV-1 enabling it to directly infect vaginal epithelial cells thereby dramatically increasing the risk of infection during sexual intercourse. We propose a molecular epidemiology study consisting of four major aims. 1) To complete in vitro studies of gammaretrovirus/HIV-1 pseudotyping; 2) To demonstrate gammaretrovirus/HIV-1 co-infections in local donors; 3) To demonstrate the effect of gammaretrovirus pseudotyping on vaginal transmission in an animal model; 4) To determine the prevalence of gammaretrovirus infection and HIV-1 co-infection in southern Africa. Natural pseudotyping of HIV-1 is predicted to occur in individuals co-infected with HIV-1 and a gammaretrovirus (XMRV/MLV) since the cellular tropism of these two viruses overlap to include T cells. The formation of XMRV-pseudoptyped HIV-1 (HIV-1/gp70) (now with the cell tropism of XMRV) in blood or lymphoid tissue would result in HIV-1 infection of normally resistant cells in the urogenital tract. Prior or subsequent infection of these cells with XMRV would result in the release of HIV-1/gp70 into seminal fluid or vaginal secretions. The potential implications of natural pseudotyping of HIV-1 are profound.