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: 8338788
• 负责人: JAMES E HILDRETH
• 金额: $ 144.55万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338788
• 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; 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 摘要： 尽管在理解HIV-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，但全球艾滋病流行病仍在继续扩大。HIV-1主要通过性接触传播，目前全世界有3 000多万人感染。在世界某些地区，如南部非洲，HIV-1感染的流行率超过20%。在这些国家，艾滋病毒-1在年轻妇女中的毁灭性传播似乎与感染的总体风险不成比例。因此，生物辅助因子可能有助于病毒传播。该建议的假设是，HIV- 1在我们称之为“自然假型化”的过程中获得了γ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的细胞嗜性，使其能够直接感染阴道上皮细胞，从而大大增加了性交期间感染的风险。我们提出了一项分子流行病学研究，包括四个主要目标。1)完成γ逆转录病毒/HIV-1假型的体外研究; 2）证明当地献血者中γ逆转录病毒/HIV-1合并感染; 3）证明γ逆转录病毒假型对动物模型阴道传播的影响; 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的天然假型化被预测发生在HIV-1和γ逆转录病毒（XMRV/MLV）共感染的个体中，因为这两种病毒的细胞嗜性重叠以包括T细胞。在血液或淋巴组织中形成XMRV假型HIV-1（HIV-1/gp 70）（现在具有XMRV的细胞嗜性）将导致HIV-1感染泌尿生殖道中的正常耐药细胞。先前或随后用XMRV感染这些细胞将导致HIV-1/gp 70释放到精液或阴道分泌物中。HIV-1天然假型化的潜在影响是深远的。