HIV-1 SHEDDING FROM FEMALE GENITAL TRACT

这是响应RFA-HD-00- 006在华盛顿大学与罗切斯特大学和肯尼亚内罗毕大学合作建立妇女艾滋病毒发病机制项目的一项新项目申请。这个项目的核心是探索女性生殖道是一个独立于血液的病毒学隔间的假设。因此，病毒在生殖隔室的应用可能受到几个因素的影响，包括宿主的激素状态（即月经），以及可能对HIV- 1的进化（即病毒多样性的产生）产生重要影响的病毒和微生物辅助因素，具有潜在耐药性的血液隔室的重新播种，以及生殖道内（从有利微生物群到不利微生物群的变化）和全身（HIV-1疾病进展）的疾病发病机制。了解这些性别特异性HIV-1因素可能为控制HIV-1的垂直和水平传播提供额外的见解。为了完成方案的中心主题，我们将使用从三个合作机构招募的三组感染艾滋病毒的妇女。本项目的研究活动将通过三个核心和三个研究项目来完成。基础设施将位于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）。内部和外部咨询委员会将审查该项目的研究进展，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，从局部阴道炎（细菌性阴道炎）到宫颈炎（巨细胞病毒），到子宫内膜炎（微生物），最终到盆腔炎，三个研究项目中的每一个都旨在捕捉这个连续体。在项目1 （HIV-1脱落和进化）中，我们将对HIV-1、CMV和HSV-2脱落的受试者进行特征描述，并通过病毒系统发育分型确定HIV-1从生殖道重新出现，并在接受稳定抗逆转录病毒治疗的受试者中重新感染血室。在项目II （CMV共脱落）中，我们将证明CMV是HIV-1脱落的独立病毒辅助因子，无论CMV从子宫颈脱落是代表再激活还是再感染，并且使用缬更昔洛韦抑制CMV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，以及在接受抗逆转录病毒治疗和未接受治疗的女性中，对细菌性阴道病进行抗微生物治疗可减少HIV-1生殖器脱落。综上所述，这些研究将为男性生殖道HIV-1的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。

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.