Characterizing Mucosal Changes in the FRT Leading to Increased HIV Acquisition

项目总结/摘要 女性生殖道的粘膜系统（FRT）是多因素的，包括上皮和粘液 屏障，高度专业化的免疫学，微生物组和激素波动来保护这个复合体 和重要器官免受病原体如艾滋病毒的攻击。任何分量的扰动 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脆弱性 性习得最近的研究表明，增加存在多个（超过3） 促炎性细胞因子是妇女感染艾滋病毒增加的一个强有力的标志。这种增加的 炎症环境与正常粘膜屏障功能的功能障碍一致。一些 这种炎症状态涉及多种因素，包括激素、微生物组和上皮细胞， 屏障破坏然而，这些炎性细胞因子的来源及其作用机制尚不清楚。 与艾滋病毒感染增加有关的问题尚不清楚。为了推进艾滋病预防科学，我们需要一个更好的 了解FRT粘膜系统。在这个项目中，我们将研究子宫切除术衍生的宫颈 肯尼亚内罗毕高危人群捐赠的组织和粘液，以了解 改变上皮和粘液屏障功能的粘膜系统。增加的炎症细胞因子 生产可以直接或间接影响组织驻留的HIV靶细胞，以增加感染的可能性。 性传播我们的假设是，靶细胞通过浸润 进入FRT的鳞状上皮，以响应增加的炎性细胞因子。我们还将 研究抗体如何潜在地增强粘液屏障功能， 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.