Quantifying the impact of genital mucosal inflammation on HIV-1 acquisition risk

描述（由申请人提供）：与性感染HIV-1相关的关键事件发生在生殖器粘膜。越来越多的研究发现，生殖器粘膜的炎症环境对HIV-1获得风险具有深远的影响：通过细菌共感染诱导促炎细胞因子和趋化因子介导HIV-1感染风险增加，而使用激素避孕可能通过减少抗炎抗蛋白酶介导HIV-1获得的影响。此外，复制HIV-1和来自HIV-1感染伴侣的精液似乎会刺激女性生殖道中的宿主介质，这些介质也会影响生殖器粘膜环境。鉴于这些关系，要详细描述主要生殖器粘膜介质及其影响HIV-1感染风险的机制，将需要通过性伴侣双方的纵向数据对这些流行病学因素进行量化。这只能通过对HIV-1血清不一致夫妇的随访来实现：对HIV-1感染和HIV-1易感伴侣的随访。

DESCRIPTION (provided by applicant): Critical events associated with sexual acquisition of HIV-1 occur in the genital mucosa. Increasingly, studies are finding that the inflammatory milieu in the genital mucosa has a profound impact on HIV-1 acquisition risk: induction of pro-inflammatory cytokines and chemokines through bacterial co-infections mediates increased risk of HIV-1 infection, while use of hormonal contraception may mediate influence on HIV-1 acquisition through reductions in anti-inflammatory anti-proteases. Furthermore, replicating HIV-1 and semen derived from the HIV-1 infected partner appear to stimulate host mediators in the female genital tract that also impact this genital mucosal environment. Given these relationships, a detailed description of the primary genital mucosal mediators and the mechanisms by which they influence HIV-1 acquisition risk will require quantification of these epidemiologic factors through longitudinal data from both sexual partners. This is only feasible through follow-up of HIV-1 serodiscordant couples: follow-up of both the HIV-1 infected and HIV-1 susceptible partner. Here we propose to use existing samples and data from a large clinical trial of oral tenofovir-based pre- exposure prophylaxis in African HIV-1 serodiscordant heterosexual couples (Partners PrEP) to quantify the most relevant genital mucosal mediators elicited in the context of well-characterized epidemiologic risk factors for HIV-1 infection. Our capacity to accomplish this is predicated on the detailed epidemiologic data collected from both sexual partners including laboratory viral sequence data from both partners facilitating confirmation of transmission linkage for all HIV-1 seroconversion events. We will use our archive of vaginal swabs and genital mucosal biopsies to facilitate a detailed quantification of genital mucosal mediators associated with these epidemiologic HIV-1 risk factors. Finally, we will test the capacity of specific genital tract mediators to predict HIV-1 acquisition risk using samples collected prior to HIV-1 infection from women who went on to seroconvert compared to HIV-1 exposed uninfected women. Through these studies we plan to quantify host genital tract mediators that modulate host susceptibility to HIV- 1 and the molecular pathways that generate them. Knowledge of these specific factors and their underlying mechanisms of action will facilitate development of novel adjuvants for modulating the host response to integrate with future HIV-1 prevention interventions.