Role of Natural Pseudotyping with Other Viruses in HIV Transmission

其他病毒的自然假型在艾滋病毒传播中的作用

• 批准号: 8897256
• 负责人: JAMES E HILDRETH
• 金额: $ 77万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897256
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Antiviral Agents; Biological; Blood; Cells; Cellular Tropism; Coitus; Country; Development; Epithelial Cells; Gammaretrovirus; Genitourinary system; Glycoproteins; HIV; HIV-1; In Vitro; Individual; Infection; Lymphoid Tissue; Molecular Epidemiology; Murine leukemia virus; Pathogenesis; Prevalence; Process; Resistance; Risk; Role; Seminal fluid; Southern Africa; T-Lymphocyte; Tropism; Vagina; Virus; abstracting; co-infection; epidemiology study; pandemic disease; transmission process; vaginal transmission; young woman

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.

描述 抽象的： 尽管在了解 HIV-1 发病机制和开发强效抗病毒药物方面取得了重大进展，但全球艾滋病流行仍在继续扩大。 HIV-1 主要通过性接触传播，目前全世界有超过 3000 万人被感染。在世界某些地区，例如南部非洲，HIV-1 感染率超过 20%。 HIV-1 在这些国家的年轻女性中的毁灭性传播似乎与总体感染风险不成比例。因此，生物辅助因子可能有助于病毒传播。该提议的假设是，HIV-1 在我们称为“自然假型”的过程中获得了伽玛逆转录病毒（鼠白血病病毒相关病毒）的包膜糖蛋白，从而扩大了 HIV-1 的细胞趋向性，使其能够直接感染阴道上皮细胞，从而大大增加性交过程中感染的风险。我们提出了一项由四个主要目标组成的分子流行病学研究。 1) 完成γ逆转录病毒/HIV-1假型的体外研究； 2) 证明当地捐献者存在γ逆转录病毒/HIV-1双重感染； 3) 在动物模型中证明γ逆转录病毒假型对阴道传播的影响； 4) 确定南部非洲γ逆转录病毒感染和HIV-1合并感染的流行率。 HIV-1 的自然假型预计会发生在同时感染 HIV-1 和伽马逆转录病毒 (XMRV/MLV) 的个体中，因为这两种病毒的细胞趋向性重叠，包括 T 细胞。血液或淋巴组织中 XMRV 假型 HIV-1 (HIV-1/gp70)（现在具有 XMRV 的细胞趋向性）的形成将导致泌尿生殖道中正常耐药细胞的 HIV-1 感染。这些细胞之前或之后感染 XMRV 会导致 HIV-1/gp70 释放到精液或阴道分泌物中。 HIV-1 自然假型的潜在影响是深远的。