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

描述(申请人提供)：在全球4000万HIV-1感染者中，近60%是女性，大多数新的HIV-1感染是通过异性接触感染的。因此，粘膜传播艾滋病毒是预防战略的最重要目标。为了设计干扰病毒传播的疫苗或局部杀微生物剂，深入了解粘膜中的初始感染事件至关重要。然而，艾滋病毒进入粘膜并在粘膜中传播的确切途径仍不清楚。特别是，缺乏澄清HIV如何与驻留在人类阴道或宫颈外上皮层的朗格汉斯和CD4+T细胞相互作用的数据。据推测，这些细胞可能是艾滋病毒的第一个敏感目标，成功地阻断它们的感染可能在中止病毒传播方面极其有效。为了解决这些问题，我们开发了一种新的人体阴道黏膜体外器官培养模型。这一模型使我们能够对HIV进入上皮内朗格汉斯和T细胞的生产性和非生产性途径进行详细的原位研究。在目标1中，我们将使用我们的模型来描述这些细胞中最初的HIV-1感染步骤。我们还将测试我们模型的变体，以允许进行临床前杀微生物剂评估所需的更高吞吐量的研究。在目标2中，我们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而不是X4嗜好的HIV-1毒株的瓶颈，从而导致了R5病毒在初次HIV感染中的优势。这些研究将产生重要的信息，使我们能够更好地了解HIV-1的粘膜传播和选择，从而对疫苗和杀微生物剂的设计有用。摘要：在世界范围内，大多数艾滋病毒感染是通过性接触后生殖器或肠道的衬里发生的。因此，需要关于这些地点最初感染事件的信息，以帮助制定预防的医疗战略，如疫苗或当地提供的抗病毒药物。在这项建议中，我们将使用从手术中获得的人类阴道组织的一种新的器官培养模型来表征艾滋病毒在性传播的最早阶段的进入途径。

DESCRIPTION (provided by applicant): 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.