Exploring HIV-Host Interactions in the Female Reproductive Tract

描述（由申请人提供）：在世界各地，妇女承担着新的艾滋病毒感染的最大负担。然而，我们对艾滋病毒在妇女中传播和发病的生物学基础的理解是不完整的。该PO 1提案的总体目标是联合一个具有互补专业知识的充满活力的研究团队，将HIV分子生物学，生殖生物学，免疫学以及临床和流行病学研究联系起来，以解决重要的未回答的问题。1)女性生殖道的哪些部位最容易感染艾滋病毒？2)哪些艾滋病毒特性和宿主因素严重影响传播率？3)内源性或外源性性激素如何影响传播频率，这些因素是否调节女性生殖道中对抗感染的先天性和适应性免疫反应？4)为什么所有测试过的阴道杀微生物剂不仅不能阻止艾滋病毒感染，而且往往导致艾滋病毒感染的矛盾增加？5)在大规模临床试验之前，能否更好地评估新的杀微生物剂候选物的安全性？我们假设：1）女性上生殖道是HIV感染的一个高度允许但研究不足的门户，2）特异性病毒（Env）和宿主（精液肽）因素对男性到女性的HIV传播的成功具有重要影响，3）性激素水平的变化（仅孕激素避孕）增强HIV传播和绝经不利地调节粘膜和全身对HIV的先天性和适应性免疫应答，4）无效和不安全的杀微生物剂激活女性上生殖道中常见的基因表达模式，创造有利于HIV传播的细胞环境。这些基因的鉴定将允许构建一个预测性的“杀微生物剂危害”的遗传标记。“这些假设将在涉及广泛的跨项目合作的三个具体目标中进行测试。具体目标1：研究调节HIV在女性上生殖道的男-女传播的病毒和宿主因素（Warner格林，医学博士，哲学博士）;具体目标2：探索女性上生殖道作为HIV传播的门户，并评估性类固醇和杀微生物剂对这些组织的影响（琳达朱迪斯，医学博士，博士，和卡伦史密斯-麦克库恩，医学博士，博士，和具体目标3：研究艾滋病毒在女性生殖道的免疫发病机制（芭芭拉沙克利特，博士）。这些研究将由两个基本核心支持，即临床和数据核心（Ruth Greenblatt，MD）和管理核心（格林博士和Greenblatt博士）。 相关性：总之，这些研究有望大大扩展我们对女性艾滋病毒传播和发病机制的分子、细胞和免疫学基础的理解。这项工作还可以推动今后努力制定有效的生物医学方法，以阻断艾滋病毒的男-女传播。

DESCRIPTION (provided by applicant): Women bear the greatest burden of new HIV infections throughout the world. Nevertheless, our understanding of the biology underlying HIV transmission and pathogenesis in women is incomplete. The overarching goal of this PO1 proposal is to unite a dynamic research team with complementary expertise that bridges HIV molecular biology, reproductive biology, immunology, and clinical and epidemiological research to address important, unanswered questions. 1) What sites in the female reproductive tract are most involved in HIV transmission? 2) What HIV properties and host factors critically affect transmission rates? 3) How do endogenous or exogenous sex hormones impact transmission frequency and do these factors modulate innate and adaptive immune responses in the female reproductive tract that counter infection? 4) Why have all tested vaginal microbicides not only failed to stop but often caused paradoxical increases in HIV infection? 5) Can the safety of new microbicide candidates be better assessed before large scale clinical testing? We hypothesize that 1) the upper female reproductive tract represents a highly permissive but understudied portal for HIV infection, 2) specific viral (Env) and host (semen peptides) factors importantly influence the success of male-to-female HIV transmission, 3) changes in sex hormone levels (progestin-only contraception) enhance HIV transmission and menopause adversely modulates both mucosal and systemic innate and adaptive immune responses to HIV, and 4) ineffective and unsafe microbicides activate common patterns of gene expression in the upper female reproductive tract, creating a cellular milieu that favors HIV transmission. Identification of these genes will permit construction of a predictive genetic signature for "microbicide harm." These hypotheses will be tested in three specific aims involving extensive cross-project collaborations. Specific Aim 1: To study viral and host factors regulating male-to-female transmission of HIV in the female upper genital tract (Warner Greene, MD, PhD); Specific Aim 2: To explore the upper female reproductive tract as a portal of HIV transmission and to assess effects of sex steroids and microbicides on these tissues (Linda Giudice, MD, PhD, and Karen Smith-McCune, MD, PhD, and Specific Aim 3: To investigate immunopathogenesis of HIV in the female reproductive tract (Barbara Shacklett, PhD). These studies will be enabled by two essential cores, the Clinical and Data Core (Ruth Greenblatt, MD) and the Administrative Core (Drs. Greene and Greenblatt). RELEVANCE: Together, these studies promise to greatly extend our understanding of the molecular, cellular, and immunological basis for HIV transmission and pathogenesis in women. This work could also propel future efforts aimed at developing effective biomedical approaches to interdict male-to-female transmission of HIV.