HIV-1 SHEDDING FROM FEMALE GENITAL TRACT

这是一项响应RFA-HD-00-006的新项目申请，旨在与肯尼亚罗切斯特大学和内罗毕大学合作，在华盛顿大学建立女性艾滋病毒致病学项目。中心计划是探索女性生殖道是从血液中分离出来的病毒学隔间这一假设。因此，病毒在生殖器间的应用可能受到几个因素的影响，包括宿主的荷尔蒙状态(即月经)，以及对艾滋病毒-1进化(即产生病毒多样性)、具有潜在抗药性的血液间隔的重新播种以及生殖道内的疾病发病机制(从有利微生物菌群变化为不利微生物菌群)和全身疾病(艾滋病毒-1疾病进展)具有重要影响的病毒和微生物辅助因素。了解这些针对性别的艾滋病毒-1因素可能会为控制艾滋病毒-1的垂直和水平传播提供更多的洞察力。为了完成中心计划的主题，我们将使用三个合作机构招募的三个不同的HIV-1感染妇女队列。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。基础设施将位于华盛顿大学的一个行政核心(核心A)、一个临床核心(核心B)和一个实验室核心(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，并向首席调查员库姆斯博士报告。由于我们的假设是生殖道炎症代表了由局部阴道炎(细菌性阴道病)、宫颈炎症(巨细胞病毒)、子宫内膜炎(微生物)以及最终到盆腔炎所定义的连续体，所以这三个研究项目中的每一个都旨在捕捉这一连续体。在项目I(艾滋病毒-1的脱落和进化)中，我们将确定艾滋病毒-1、巨细胞病毒和单纯疱疹病毒-2的脱落对象的特征，并通过病毒系统发育分型最终确定在接受稳定的抗逆转录病毒治疗的对象中，艾滋病毒-1从生殖道重新出现并再次感染血液隔间。在项目II(CMV共同脱落)中，我们将展示CMV是HIV-1脱落的一个独立的病毒辅助因素，无论CMV从宫颈脱落代表重新激活还是再次感染，使用valganciclovir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影响，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，以及在抗逆转录病毒治疗和未治疗的妇女中，细菌性阴道病的抗微生物治疗可以减少HIV-1生殖器脱落。综上所述，这些研究将为男性生殖道中艾滋病毒-1的脱落提供重要的比较数据，并可能对艾滋病毒-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.