Elucidating mechanisms of HIV-1 mucosal transmission

项目摘要/摘要 自1983年首次被发现以来，艾滋病毒/艾滋病一直在无情地传播，造成了最具破坏性的 人类历史上最大的流行病。历史上对传染病的描述表明，它们可以有一个重大的 对美国武装部队的影响。全球有3400万人感染艾滋病毒，HIV-1对 对许多民族国家的武力准备和稳定构成持续威胁。艾滋病毒/艾滋病感染的发生率 在美国服务人员中，通过异性性交接触艾滋病毒-1的风险很大 退伍军人和服役人员中的比例要大得多。HIV-1从男性到女性的异性传播 占全球新感染病例的大多数，值得注意的是，妇女在 一个不断增长的速度。缺乏对妇女有效的预防模式阻碍了对妇女有效预防模式的发现 关于女性生殖道粘膜中早期病毒与宿主相互作用的信息，这是获得 HIV-1感染。HIV/SIV传播的非人灵长类(NHP)模型表明，巨噬细胞和 主要是CD4T细胞在大剂量阴道内攻击后的头几天内被感染。 对早期CD4T细胞感染的观察似乎与随后发表的工作一致，表明 传播型/方正(TF)病毒一般对单核细胞来源的巨噬细胞表现出低至中等的趋向性 (MDM)。然而，最近公布和未公布的数据(初步研究)会认为，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 调查。我们的中心假设是，宫颈巨噬细胞需要驱动HIV-1的复制和 扩散到宫颈粘膜。我们的推论假设，尽管超出了这一直接范围 应用，是宫颈巨噬细胞(CmφS)是HIV-1感染的扩张和传播所必需的 在粘膜中受感染的CD4T细胞的初始病灶之外，因此代表着一个潜在的决定因素 HIV-1在女性粘膜中的异性传播。为了验证这一中心假设，我们提出了 具体目标如下：(1)描述HIV-1在人类宫颈中感染和复制的动态 外植体组织；(2)确定未感染和感染HIV-1的CmφS之间的时空关系 和宫颈组织中CD4T淋巴细胞的原位表达；(3)确定CM-φS的细胞决定因素 对HIV-1感染的敏感性。我们的研究承诺阐明关键的病毒与宿主之间的相互作用 女性生殖道粘膜感染HIV-1的建立。对我们的中心假设的验证 将带来该领域的范式转变，并暗示cmφS是新发现的可行的早期目标 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 However, recent published and unpublished data (Preliminary Studies) would argue that this central question regarding HIV-1 transmission biology, and the role of macrophages in particular, warrants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.