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

量化生殖器粘膜炎症对 HIV-1 感染风险的影响

基本信息

批准号：
8704081
负责人：
Jairam Rao Lingappa
金额：
$ 56.92万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-05 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704081
关键词：
Adjuvant African Anti-Inflammatory Agents Anti-inflammatory Archives Bacterial Vaginosis Biological Assay Biopsy CCR5 gene Cells Cervical Clinical Trials Complex Couples Data Dendritic Cells Development Enrollment Environment Epidemiologic Factors Epidemiology Evaluation Event Exposure to Female Frequencies Future Gene Chips Gene Expression Genital system HIV-1 Heterosexuals IL8 gene Immune response Individual Infection Inflammation Inflammation Mediators Inflammatory Injectable Interleukin-1 Knowledge Laboratories Mediating Mediator of activation protein Medroxyprogesterone 17-Acetate Molecular Mucositis Mucous Membrane Oral Pathway interactions Peptide Hydrolases Placebos Plasma Predisposition Preventive Intervention Prophylactic treatment Risk Risk Factors Sampling Seminal fluid Sexual Partners Sexual Transmission Sexually Transmitted Diseases Swab T-Lymphocyte TNF gene Tenofovir Testing Tissues Unsafe Sex Vagina Viral Visit Woman base chemokine cohort cytokine epidemiologic data follow-up genital secretion high risk hormonal contraception immune activation inflammatory marker microbiome novel novel virus public health relevance response sex transmission process

项目摘要

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.

描述（由申请人提供）：与性行为获得 HIV-1 相关的关键事件发生在生殖器粘膜中。越来越多的研究发现，生殖器粘膜中的炎症环境对 HIV-1 感染风险具有深远影响：通过细菌合并感染诱导促炎细胞因子和趋化因子会介导 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来介导对 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，从而影响生殖器粘膜环境。鉴于这些关系，对主要生殖器粘膜介质及其影响 HIV-1 感染风险的机制的详细描述将需要通过来自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 血清不一致的夫妇进行随访才可行：对 HIV-1 感染者和 HIV-1 易感性伴侣进行随访。在这里，我们建议使用来自非洲 HIV-1 血清不一致异性夫妇（合作伙伴 PrEP）的基于口服替诺福韦的暴露前预防的大型临床试验的现有样本和数据来量化在良好的背景下引发的最相关的生殖器粘膜介质。描述了 HIV-1 感染的流行病学危险因素。我们实现这一目标的能力取决于从性伴侣收集的详细流行病学数据，包括来自性伴侣的实验室病毒序列数据，有助于确认所有 HIV-1 血清转化事件的传播联系。我们将利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病学 HIV-1 危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介质预测 HIV-1 感染风险的能力。与暴露于 HIV-1 的未感染女性相比，随后发生血清转化的女性感染 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介质以及产生它们的分子途径。了解这些特定因素及其潜在作用机制将有助于开发新型佐剂，用于调节宿主反应，从而与未来的 HIV-1 预防干预措施相结合。