Mechanisms of HIV-1 Transmission in the Genital Mucosa of Women

全世界4000万HIV-1感染者中近60%是女性，大多数新的HIV-1感染者都是女性。 感染是通过异性性接触传染的。因此，艾滋病毒的粘液传播是最重要的 预防战略的目标。设计疫苗或局部杀微生物剂， 因此，深入了解粘膜中的初始感染事件至关重要。 然而，HIV进入粘膜并在粘膜中传播的确切途径仍然不清楚。在 特别是，缺乏数据来阐明HIV如何与位于细胞内的朗格汉斯和CD 4 + T细胞相互作用。 人阴道或子宫颈外的外上皮层。这些细胞大概是第一个 艾滋病毒的靶点，并成功阻断其感染， 传输为了解决这些问题，我们开发了一种新的人类离体器官培养模型， 阴道粘膜这种模式使我们能够进行详细的生产和非生产性的现场调查， HIV进入上皮内朗格汉斯和T细胞的生产途径。在目标1中，我们将使用 模型来表征这些细胞中HIV-1感染的初始步骤。我们还将测试我们的模型的变化 这可以允许临床前杀微生物剂评价所需的更高通量研究。在目标2中， 将确定上皮内朗格汉斯和T细胞的感染是否构成了有利于R5的瓶颈。 X4嗜性HIV-1毒株，因此导致原发性HIV期间R5病毒占优势 感染这些研究将产生重要的信息，使我们能够更好地了解粘膜HIV-1 传播和选择，因此将有助于疫苗和杀微生物剂的设计。 简单摘要： 在世界范围内，大多数艾滋病毒感染是通过性行为后的生殖器或肠道内壁发生的。 contact.因此，需要关于这些地点的初始感染事件的信息来帮助设计 预防的医疗策略，如疫苗或当地提供的抗病毒药物。在本提案中，我们 将使用从手术中获得的人类阴道组织的新型器官培养模型来表征 艾滋病毒在性传播的最早阶段进入途径。

Almost 60% of the 40 million HIV-1 infected individuals worldwide are women, and most new HIV-1 infections are contracted by heterosexual contact. Mucosal HIV transmission is therefore the most important target for preventative strategies. To design vaccines or topical microbicides that interfere with viral transmission, it is critical to have an in-depth understanding of the initial infection events in the mucosa. However, the exact pathways whereby HIV enters and propagates in the mucosa remain ill defined. In particular, data are lacking that clarify how HIV interacts with Langerhans and CD4+ T cells that reside in the outer epithelial layer of the human vagina or ectocervix. These cells are presumably the first susceptible targets for HIV, and a successful blockade of their infection could be extremely effective in aborting viral transmission. To address these issues, we developed a novel ex vivo organ culture model of the human vaginal mucosa. This model allows us to perform detailed in situ investigations of the productive and non- productive pathways for entry of HIV into intraepithelial Langerhans and T cells. In Aim 1, we will use our model to characterize the initial HIV-1 infection steps in these cells. We will also test variations of our model that may allow for higher throughput studies as required for preclinical microbicide evaluation. In Aim 2, we will determine if infection of intraepithelial Langerhans and T cells constitutes a bottleneck favoring R5- over X4-tropic HIV-1 strains, therefore contributing to the predominance of R5 viruses during primary HIV infection. These studies will yield important information that will allow us to better understand mucosal HIV-1 transmission and selection, and will thus be useful for vaccine and microbicide design. Lay abstract: Worldwide, most HIV infections occur through the linings of the genital or intestinal tract following sexual contact. Information about the initial infection events at these sites is therefore needed to help in devising medical strategies for prevention, such as vaccines or locally delivered antiviral drugs. In this proposal, we will use a novel organ culture model of human vaginal tissue obtained from surgeries to characterize the entry pathways of HIV during the earliest stages of sexual transmission.