Characterizing Mucosal Changes in the FRT Leading to Increased HIV Acquisition

项目摘要/摘要 女性生殖道的粘膜系统是多因素的，由上皮和粘液组成。 屏障，高度专业化的免疫学，微生物组，和荷尔蒙波动来保护这个复合体 和必要的器官免受病原体的攻击，如艾滋病毒。它的任何组成部分的微扰 该系统有可能降低屏障功能，同时可能增加妇女对艾滋病毒的易感性 性获得。最近的研究表明，多个(3个以上)的存在增加 促炎细胞因子是女性艾滋病毒感染增加的强烈标志。这增加了 炎症环境与正常黏膜屏障功能障碍相一致。一批 包括激素、微生物组和上皮细胞在内的多种因素与这种炎症状态有关 障碍物破坏。然而，这些炎性细胞因子的来源及其机制 与艾滋病毒获得率增加有关的问题尚不清楚。为了推进艾滋病毒预防科学，我们需要一个更好的 了解FRT黏膜系统。在这个项目中，我们将检查源自宫颈的子宫切除术。 肯尼亚内罗毕高危人群捐赠的组织和粘液，以深入了解 改变上皮和粘液屏障功能的粘膜系统。炎性细胞因子升高 生产可直接或间接影响组织内驻留的HIV靶细胞增加感染几率 性传播。我们的假设是，靶细胞通过渗透变得更容易感染艾滋病毒 进入FRT的鳞状上皮，以应对炎性细胞因子的增加。我们还将 研究抗体如何潜在地增强粘液屏障功能潜在地揭示了一种新的 艾滋病毒疫苗开发战略。

Project Summary/Abstract The mucosal system of the female reproductive tract (FRT) is multifactorial, combining epithelial and mucus barriers, a highly specialized immunology, the microbiome, and hormonal fluctuations to protect this complex and essential organ from attack by pathogen’s such as HIV. Perturbation of any of the components of this system has the potential to decrease barrier function while potentially increasing a woman’s vulnerability to HIV sexual acquisition. Recent studies have revealed that an increase in the presence of multiple (more than 3) pro-inflammatory cytokines are a strong signature of increased HIV acquisition in women. This increased inflammatory environment is consistent with the dysfunction of normal mucosal barrier function. A number of factors have been implicated in this inflammatory state including hormones, the microbiome, and epithelial barrier disruption. However, the origin of these inflammatory cytokines and the mechanism of how they are related to increased HIV acquisition is not understood. To advance HIV prevention science, we need a better understanding of the FRT mucosal system. In this project we will examine hysterectomy derived cervical tissues and mucus donated by high-risk populations in Nairobi, Kenya to gain insight into the changes in the mucosal system that alters epithelial and mucus barrier function. The increased Inflammatory cytokine production can directly or indirectly influence tissue resident HIV target cells to increase the probability of sexual transmission. Our hypothesis is that target cells become more susceptible to HIV infection by infiltrating into the squamous epithelium of the FRT in response to the increased inflammatory cytokines. We will also examine how antibodies can potentially enhance the mucus barrier function potentially revealing a novel strategy for HIV vaccine development.