MAbs in the Cervicovaginal Environment: Cellular Interactions and Host Defense

一种安全、可获得和有效的局部杀微生物剂可以大大降低艾滋病毒的性传播率，并有可能挽救数百万人的生命。人单克隆抗体（mAb）具有高效力、特异性和可接受的安全性，并且是用于包含在局部杀微生物剂中的主要候选者。项目2的目的是鉴定靶向HIV-1传播的不同方面的多种mAb（4 E10、VRC 01和抗HSVgD）在宫颈阴道环境中起作用的机制。在具体目标1中，我们将研究单克隆抗体与阴道上皮细胞的相互作用。我们将使用人阴道组织和MatTek EpiVaginal器官型组织模型来确定Mab摄取和释放药效学和动力学、Mab渗透深度和分布、对促炎细胞因子和先天免疫介质的影响以及阴道上皮细胞对HSV和HIV感染的Mab保留的影响。我们还将在这些检测系统中检测宫颈粘液和精液对mAb抗病毒效力的影响。在具体目标2中，我们将研究mAb对细胞相关HIV传播的影响。在具体目标3中，我们将研究单克隆抗体在对猕猴和女性阴道给药后的离体功效。与临床项目合作，我们还将研究在女性中使用mapp 66杀微生物剂薄膜对阴道炎症和先天免疫标志物的影响。这些数据，当与其他IPCP项目和核心的数据相结合，应该为单克隆抗体为基础的阴道杀微生物剂的进步提供了坚实的基础。

A safe, accessible and effective topical microbicide could significantly reduce the rate of HIV sexual transmission and potentially save millions of lives. Human monoclonal antibodies (mAbs) have high potency, specificity and an acceptable safety profile, and are leading candidates for inclusion in topical microbicides. The objective of Project 2 is to identify mechanisms by which diverse mAbs targeting different aspects of HIV-1 transmission (4E10, VRCOl, and anti-HSVgD) operate in the cervicovaginal environment. In Specific Aim 1 we will study Mab interactions with vaginal epithelial cells. We will use human vaginal tissue and the MatTek EpiVaginal organotypic tissue model to determine Mab uptake and release pharmacodynamics and kinetics, Mab penetration depth and distribution, effects on proinflammatory cytokines and mediators of innate immunity, and effects of Mab retention by vaginal epithelial cells on HSV and HIV infection. We will also test the effects of cervical mucus and semen on mAb antiviral efficacy in these assay systems. In Specific Aim 2 we will study the effects of mAbs on cell-associated HIV transmission . In Specific Aim 3 we will study ex vivo efficacy of Mabs following vaginal administration to macaques and women. In collaboration with the clinical project, we will also study effects of mapp66 microbicide film use in women on markers of vaginal inflammation and innate immunity. These data, when combined with data from the other IPCP projects and cores, should provide a solid foundation for the advancement Mab-based vaginal microbicides.