MAbs in the Cervicovaginal Environment: Cellular Interactions and Host Defense

一种安全、可及和有效的局部杀微生物剂可以显著降低艾滋病毒的性传播率，并可能挽救数百万人的生命。人单克隆抗体（mab）具有高效、特异性和可接受的安全性，是局部杀菌剂的主要候选物。项目2的目标是确定针对HIV-1传播不同方面（4E10、VRCOl和抗hsvgd）的多种单克隆抗体在宫颈阴道环境中的作用机制。在特异性目标1中，我们将研究Mab与阴道上皮细胞的相互作用。我们将使用人类阴道组织和MatTek外阴器官型组织模型来确定Mab摄取和释放的药效学和动力学，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，以及阴道上皮细胞保留Mab对HSV和HIV感染的影响。我们还将在这些检测系统中测试宫颈粘液和精液对单抗抗病毒效果的影响。在特异性目标2中，我们将研究单克隆抗体对细胞相关HIV传播的影响。在特异性目标3中，我们将研究单抗阴道给药后对猕猴和女性的体外疗效。在与临床项目的合作中，我们还将研究在女性中使用mapp66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项目和核心数据相结合时，应该为推进基于单抗的阴道杀微生物剂提供坚实的基础。

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.