HIV-1 SHEDDING FROM FEMALE GENITAL TRACT

HIV-1 从女性生殖道脱落

• 批准号: 6657925
• 负责人: Robert W. Coombs
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-23 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657925
• 关键词: HIV infections; communicable disease transmission; female; genital secretion; human immunodeficiency virus 1; human subject; microorganism population study; patient oriented research; virus infection mechanism; women's health

This is a new Program Project application in response to RFA-HD-00- 006 to establish a Women's HIV Pathogenesis program at the University of Washington in collaboration the University of Rochester and the University of Nairobi, Kenya. The central Program these is to explore the hypothesis that the female genital tract is a separate virological compartment from blood. As such, viral application in the genital compartment may be influenced by several factors including the host's hormonal status (i.e., menses), and both viral and microbiological cofactors that could have an important influence on the evolution of HIV- 1 (i.e., generation of viral diversity), re-seeding of the blood compartment with potentially drug-resistant, and disease pathogenesis both within the genital tract (changes from favorable to unfavorable microbiological flora) and systemically (HIV-1 disease progression). Understanding these gender-specific HIV-1 factors may provide additional insight into the control of both vertical and horizontal transmission of HIV-1. To accomplish the central Program theme, we will use three different cohorts of HIV-1-infected women recruited at the three collaborating institutions. The research activities of the Program Project will be accomplished through three Cores and three Research Projects. The infrastructure will reside within an Administrative Core (Core A) located at the University of Washington, a Clinical Core (Core B) and a Laboratory Core (Core C). Both internal and external advisory committees will review the Program's research progress and report to the Principal Investigator, Dr. Coombs. Since our hypothesis is that genital tract inflammation represents a continuum as defined by local vaginitis (bacterial vaginosis), to cervicitis (cytomegalovirus), to endometritis (microbial) and ultimately to pelvic inflammatory disease, each of the three research Projects are designed to capture this continuum. In Project I (HIV-1 shedding and evolution), we will characterize subjects for shedding of HIV-1, CMV and HSV-2, and definitively establish, through viral phylogenetic typing that HIV-1- re-emerges from the genital tract to re-infect the blood compartment in subjects that receive stable anti- retroviral therapy. In Project II (CMV co-shedding) we will show that CMV is an independent viral co-factor for HIV-1 shedding, whether CMV shedding from the cervix represents reactivation or re-infection, and that the suppression of CMV using valganciclovir can decrease HIV- 1 genital shedding. In Project III( Bacterial Vaginosis), we will show the effect of bacterial vaginosis as a local co-factor for HIV-1 shedding, how this local abnormal microbiological flora contributes to HIV-1 shedding through local cytokine-mediated mechanisms, and that anti-microbial treatment of bacterial vaginosis in both anti-retroviral treated and untreated women results in decreased HIV-1 genital shedding. Taken together, these studies will provide important comparative data to the male genital tract shedding of HIV-1 and may have implications for both the vertical and horizontal transmission of HIV-1.

这是响应 RFA-HD-00-006 的一项新计划项目申请，旨在与罗切斯特大学和肯尼亚内罗毕大学合作，在华盛顿大学建立女性艾滋病毒发病机制计划。这些中心计划是探索女性生殖道是与血液分开的病毒学隔室的假设。因此，病毒在生殖器中的应用可能受到多种因素的影响，包括宿主的激素状态（即月经），以及可能对 HIV-1 的进化产生重要影响的病毒和微生物辅助因子（即，HIV-1 的产生）。病毒多样性）、具有潜在耐药性的血液隔室的重新播种以及生殖道内的疾病发病机制（从有利微生物菌群到不利微生物菌群的变化）以及系统性（HIV-1 疾病进展）。了解这些针对性别的 HIV-1 因素可能会为控制 HIV-1 的垂直和水平传播提供更多见解。为了实现中心计划主题，我们将使用在三个合作机构招募的三个不同的 HIV-1 感染女性群体。该计划项目的研究活动将通过三个核心和三个研究项目来完成。该基础设施将驻留在华盛顿大学的行政核心（核心 A）、临床核心（核心 B）和实验室核心（核心 C）内。内部和外部咨询委员会将审查该计划的研究进展并向首席研究员库姆斯博士报告。由于我们的假设是，生殖道炎症代表了一个连续体，定义为局部阴道炎（细菌性阴道病）、宫颈炎（巨细胞病毒）、子宫内膜炎（微生物）以及最终盆腔炎，因此三个研究项目中的每一个都旨在捕捉这一点连续体。在项目 I（HIV-1 脱落和进化）中，我们将描述脱落 HIV-1、CMV 和 HSV-2 的受试者特征，并通过病毒系统发育分型明确确定 HIV-1- 从生殖道重新出现到重新感染接受稳定抗逆转录病毒治疗的受试者的血液室。在项目II（CMV共同脱落）中，我们将证明CMV是HIV-1脱落的独立病毒辅助因子，无论CMV从宫颈脱落代表重新激活还是再次感染，以及使用缬更昔洛韦对CMV的抑制可以减少HIV-1 生殖器脱落。在项目 III（细菌性阴道病）中，我们将展示细菌性阴道病作为 HIV-1 脱落的局部辅助因素的作用，这种局部异常微生物菌群如何通过局部细胞因子介导的机制促进 HIV-1 脱落，以及抗病毒药物-对接受抗逆转录病毒治疗和未接受治疗的女性细菌性阴道病进行微生物治疗可减少 HIV-1 生殖器脱落。总而言之，这些研究将为男性生殖道 HIV-1 脱落提供重要的比较数据，并可能对 HIV-1 的垂直和水平传播产生影响。