Immune mediators associated with HPV clearance as predictors of HIV acquisition

 描述(申请人提供)：生殖器人类乳头瘤病毒(HPV)是最常见的性传播感染之一。最近的一项荟萃分析证实，除了作为宫颈癌和几种肛门生殖器癌发生的必要因素外，HPV还与艾滋病毒感染风险增加高达5倍有关。值得注意的是，这种影响在最近清除了HPV感染的人中更加明显。到目前为止，还没有系统地设计研究来确定清除HPV可能有助于感染HIV的潜在粘膜机制。我们认为，与检测和应对HPV感染相关的分子和免疫学事件，包括粘膜产生HPV特异性抗体，激活的T细胞和NK细胞的招募，以及上皮完整性的破坏，也可能是随后感染HIV的辅助因素。我们建议利用正在进行的CAPRISA 008试验的数据来检验这一假设，该试验测试了将1%替诺福韦凝胶供应整合到计划生育诊所的可行性。具体来说，我们 将：1)描述与HPV清除相关的细胞和体液免疫反应，以及生殖器上皮完整性水平；以及2)比较感染HIV者和未感染HIV者HPV清除的粘膜相关性。HPV感染不会导致病毒血症；而且血清转换只发生在大约60%的个体中，而且即使是这样，也只是在自然感染的后期发生。尽管这些观察结果强调了了解生殖器HPV感染局部反应的重要性，但HPV感染的粘膜免疫学仍然知之甚少。这项前瞻性研究提供了一个理想的机会，让我们更好地了解清除HPV感染和增强HIV感染之间的强大流行病学联系的生物学基础。撒哈拉以南非洲HPV感染的高流行率，加上8-12个月内HPV的高清除率，将加强我们对其对艾滋病毒感染的相对贡献的了解，并为设计适当的干预措施以降低艾滋病毒获得率提供信息。更好地了解生殖器HPV感染清除与艾滋病毒感染之间的关系对于解决更大的研究问题至关重要，这些研究问题包括：(1)如何限制常见HPV感染对艾滋病毒的有害影响；(2)考虑到复杂的粘膜免疫反应，如随时间推移的粘膜免疫反应、HPV感染的数量和类型以及其他风险因素，HPV疫苗接种是否有可能影响艾滋病毒发病率。通过加强对构成令人信服和一致的流行病学证据的生物学机制的了解，我们可以开始确定和通报适当的、有针对性的和具体的艾滋病毒预防干预措施。

 DESCRIPTION (provided by applicant): Genital human papillomavirus (HPV) is one of the most common sexually transmitted infections. In addition to its role as a necessary factor in the development of cervical and several anogenital cancers, a recent meta-analysis confirms that HPV is associated with up to 5-fold increased risk of HIV acquisition. Notably, this effect was even more pronounced among individuals who had recently cleared an HPV infection. Thus far no study has been systematically designed to determine potential mucosal mechanisms by which clearance of HPV may facilitate acquisition of HIV. We propose that molecular and immunological events associated with the detection and response to HPV infection, including mucosal production of HPV-specific antibodies, recruitment of activated T and NK cells, and disrupted epithelial integrity, may also serve as co-factors for subsequent HIV acquisition. We propose to test this hypothesis utilizing data from the ongoing CAPRISA 008 trial that tests the feasibility of integrating 1% tenofovir gel provision into family planning clinics. Specifically we will: 1) characterize the cellular and humoral immune responses, and level of genital epithelial integrity associated with HPV clearance; and 2) compare these mucosal correlates of HPV clearance in those who acquire HIV compared to those who do not acquire HIV. HPV infection does not cause viremia; and seroconversion only occurs in about 60% of individuals, and even then only late in natural infection. Despite these observations underscoring the importance of understanding local responses to genital HPV infection the mucosal immunology of HPV infection is still poorly understood. This prospective study provides an ideal opportunity to bette understand the biological underpinnings of the strong epidemiological association between the clearance of HPV infection and enhanced HIV acquisition. The high prevalence of HPV infection in sub- Saharan Africa, together with high HPV clearance rates within 8-12 months, will enhance our understanding of its relative contribution to HIV acquisition and inform the design of appropriate interventions to reduce HIV acquisition rates. A better understanding of the associations between clearance of genital HPV infection and HIV acquisition is critical to addressing larger research questions that include (1) how to limit a deleterious effect of common HPV infections on HIV and (2) whether HPV vaccination has the potential to impact HIV incidence, taking into consideration complexities such as mucosal immune responses over time, number and type of HPV infections, and other risk factors. By enhancing understanding of the biological mechanism that underpins the compelling and consistent epidemiological evidence we can begin to identify and inform appropriate, targeted and specific HIV prevention interventions.