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相关的危急事件发生在生殖器粘膜。越来越多的研究发现，生殖器粘膜中的炎症环境对HIV-1感染的风险有深远的影响：通过细菌混合感染诱导促炎细胞因子和趋化因子会增加HIV-1感染的风险，而激素避孕的使用可能通过减少抗炎抗蛋白水解酶来调节对HIV-1感染的影响。此外，复制HIV-1和来自HIV-1感染伴侣的精液似乎刺激了女性生殖道中的宿主介体，这也影响了这种生殖器粘膜环境。鉴于这些关系，对主要生殖器粘膜介体及其影响艾滋病毒-1感染风险的机制的详细描述将需要通过来自双方性伴侣的纵向数据来量化这些流行病学因素。这只有通过对HIV-1血清不一致夫妇的后续行动才是可行的：对HIV-1感染者和HIV-1易感配偶的后续行动。 在这里，我们建议使用现有的样本和来自非洲HIV-1血清不一致异性伴侣(Partners PrEP)的基于替诺福韦的暴露前口服预防的大型临床试验的数据来量化在HIV-1感染的流行病学风险因素的背景下引发的最相关的生殖器粘膜介质。我们实现这一目标的能力是基于从双方性伴侣那里收集的详细流行病学数据，包括从双方那里收集的实验室病毒序列数据，这有助于确认所有HIV-1血清转换事件的传播联系。我们将使用我们的阴道拭子和生殖器粘膜活检档案来促进与这些流行的HIV-1风险因素相关的生殖器粘膜介质的详细量化。最后，我们将使用之前收集的样本来测试特定生殖道媒介预测HIV-1感染风险的能力 与接触HIV-1的未感染妇女相比，后来血清转换的妇女感染了HIV-1。 通过这些研究，我们计划量化调节宿主对HIV-1易感性的宿主生殖道媒介以及产生它们的分子途径。了解这些特定因素及其潜在的作用机制将有助于开发新的佐剂，用于调节宿主的反应，以便与未来的艾滋病毒-1预防干预措施相结合。

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.