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

• 批准号: 8817239
• 负责人: Jairam Rao Lingappa
• 金额: $ 59.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8817239
• 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; Health; 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; co-infection; cohort; cytokine; epidemiologic data; follow-up; genital secretion; high risk; hormonal contraception; immune activation; inflammatory marker; microbiome; novel; novel virus; response; seroconversion; sex; transmission process

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HIV-1性获得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感染风险具有深远的影响：通过细菌合并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质，这些介质也影响了生殖器粘膜环境。鉴于这些关系，详细描述的主要生殖器粘膜介质和机制，它们影响HIV-1的收购风险将需要量化这些流行病学因素，通过纵向数据从双方的性伴侣。这只有通过对HIV-1血清不一致的夫妇进行随访才是可行的：对HIV-1感染者和HIV-1易感者的伴侣进行随访。 在这里，我们建议使用现有的样本和数据，从一个大的临床试验口服替诺福韦为基础的暴露前预防非洲HIV-1血清不一致的异性恋夫妇（合作伙伴PrEP），以量化最相关的生殖器粘膜介质引起的背景下，充分表征的流行病学风险因素的HIV-1感染。我们实现这一目标的能力是基于从性伴侣双方收集的详细流行病学数据，包括从性伴侣双方收集的实验室病毒序列数据，这些数据有助于确认所有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，以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定量。最后，我们将测试特定的生殖道介质的能力，以预测HIV-1的获得风险，使用之前收集的样本， 与HIV-1暴露的未感染妇女相比，HIV-1感染的妇女继续血清转化。 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的作用机制将有助于开发新的佐剂，用于调节宿主反应，以与未来的HIV-1预防干预措施相结合。