Elucidating mechanisms of HIV-1 mucosal transmission

项目概要/摘要 自1983年首次发现艾滋病毒/艾滋病以来，它一直在无情地蔓延，造成了世界上最具破坏性的疾病之一。 人类历史上最大的传染病传染病的历史记载表明， 对美国武装部队的影响。全世界有3400万人感染HIV-1， 对许多民族国家的武力准备和稳定的持续威胁。艾滋病毒/艾滋病感染率 在美国服务人员中，通过异性性交暴露于HIV-1的风险很大， 在退伍军人和服务人员中的比例要大得多。HIV-1从男性向女性的异性性传播 占全球新感染病例的大多数，值得注意的是， 增长率。由于缺乏基本的知识， 关于女性生殖道粘膜中早期病毒-宿主相互作用的信息， HIV-1感染。HIV/SIV传播的非人灵长类动物（NHP）模型表明，巨噬细胞和 主要是CD 4 T细胞在高剂量阴道内攻击后的最初几天内被感染。 早期CD 4 T细胞感染的观察结果似乎与随后发表的工作一致，表明 传播/创始者（TF）病毒通常表现出对单核细胞衍生的巨噬细胞的低至中度嗜性 （MDM）。然而，最近发表和未发表的数据（初步研究）认为，这一中心 关于HIV-1传播生物学的问题，特别是巨噬细胞的作用，需要额外的研究。 调查我们的中心假设是，宫颈巨噬细胞是驱动HIV-1复制所必需的， 在宫颈粘膜中扩散。我们的推论假设，尽管超出了这个的直接范围 宫颈巨噬细胞（cMφs）是HIV-1感染的扩展和传播所必需的 除了粘膜中受感染的CD 4 T细胞的初始病灶之外，因此代表了感染的潜在决定因素。 粘膜HIV-1异性性传播的妇女。为了质疑这一中心假设，我们提出了 （1）研究人宫颈癌组织中HIV-1感染和复制的动态变化， （2）确定未感染和HIV-1感染的cMφ之间的时空关系 （3）确定cMφs的细胞决定簇 易感染HIV-1。我们的研究有望阐明关键的病毒-宿主相互作用， 在女性生殖道粘膜中建立HIV-1感染。验证我们的中心假设 这将在该领域带来范式转变，并暗示cMφ是发现新的 艾滋病毒/艾滋病预防战略。

Project Summary/Abstract HIV/AIDS has spread relentlessly since it was first identified in 1983, causing one of the most devastating pandemics in human history. Historical accounts of infectious diseases show that they can have a major impact on U.S. Armed Forces. With 34 million individuals infected worldwide, HIV-1 poses a significant and persistent threat to force readiness and the stability of many nation-states. The incidence of HIV/AIDS infection among U.S. service personnel is significant and the risk of exposure to HIV-1 by heterosexual intercourse among veterans and service personnel is much greater. Heterosexual HIV-1 transmission from men to women accounts for the majority of new infections worldwide, and notably, women are entering into military service at an increasing rate. The discovery of effective prevention modalities for women is hindered by a lack of basic information about early virus-host interactions in the female genital tract mucosa that underlie the acquisition of HIV-1 infection. Non-human primate (NHP) models of HIV/SIV transmission indicate that macrophages and predominantly CD4 T cells become infected within the first few days after high-dose intravaginal challenge. The observation of early CD4 T cell infection seemed consistent with subsequent published work indicating transmitted/founder (TF) viruses generally exhibit low to moderate tropism for monocyte-derived macrophages (MDM). However, recent published and unpublished data (Preliminary Studies) would argue that this central question regarding HIV-1 transmission biology, and the role of macrophages in particular, warrants additional investigation. Our central hypothesis is that cervical macrophages are required to drive HIV-1 replication and spread in the cervical mucosa. Our corollary hypothesis, though beyond the immediate scope of this application, is that cervical macrophages (cMφs) are required for expansion and spread of HIV-1 infection beyond initial foci of infected CD4 T cell in the mucosa, and thus represent an underlying determinant of mucosal HIV-1 heterosexual transmission in women. To interrogate this central hypothesis, we propose the following specific aims: (1) To characterize the dynamics of HIV-1 infection and replication in human cervical explant tissue; (2) To determine the spatiotemporal relationships between uninfected and HIV-1 infected cMφs and CD4 T lymphocytes in cervical tissue in situ; and (3) To identify cellular determinants of cMφs susceptibility to HIV-1 infection. Our research promise to elucidate critical virus-host interactions that underlie the establishment of HIV-1 infection in the female mucosal genital tract. Validation of our central hypothesis would impart a paradigm shift in the field, and implicate cMφs as a viable early target for the discovery of new HIV/AIDS prevention strategies.