Immune mediators associated with HPV clearance as predictors of HIV acquisition

与 HPV 清除相关的免疫介质可作为 HIV 感染的预测因子

• 批准号: 8992353
• 负责人: DAVID D. CELENTANO
• 金额: $ 18.65万
• 依托单位: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992353
• 关键词: AIDS prevention; Address; Affect; Africa South of the Sahara; Anogenital cancer; Anogenital venereal warts; Antibodies; Antibody Response; Biological; Biological Markers; Biological Response Modifiers; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Clinic; Cohort Studies; Data; Detection; Development; Enrollment; Environment; Epidemiology; Epithelial; Epithelium; Event; Family Planning; Future; Gel; Genital Human Papilloma Virus Infection; Genital system; HIV; HIV Infections; HIV risk; Health; Helper-Inducer T-Lymphocyte; High Prevalence; Human Papilloma Virus Vaccination; Human Papillomavirus; Human papilloma virus infection; Immune; Immune response; Immunology; Incidence; Individual; Infection; Inflammatory Response; Intervention; Link; Malignant neoplasm of cervix uteri; Measures; Mediating; Meta-Analysis; Metabolic Clearance Rate; Molecular; Mucosal Immune Responses; Natural History; Natural Killer Cells; Oncogenic; Participant; Pathway interactions; Personal Communication; Predisposition; Prevalence; Preventive Intervention; Production; Prospective Studies; Public Health; Research; Risk; Risk Factors; Role; Sexually Transmitted Diseases; Source; South Africa; T-Lymphocyte; Tenofovir; Testing; Time; Tissues; Vagina; Viremia; Virus; Virus Diseases; Woman; cellular targeting; cervicovaginal; cohort; design; hazard; improved; non-oncogenic; pathogen; prospective; response; seroconversion; sexual HIV transmission

 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.

 描述（由申请人提供）：生殖器人乳头瘤病毒（HPV）是最常见的性传播感染之一。除了作为宫颈癌和几种肛门生殖器癌发生的必要因素外，最近的一项荟萃​​分析证实，HPV 与艾滋病毒感染风险增加 5 倍相关。值得注意的是，这种效应在最近清除 HPV 感染的个体中更为明显。迄今为止，还没有系统设计的研究来确定清除 HPV 可能促进艾滋病毒感染的潜在粘膜机制。我们认为，与 HPV 感染的检测和反应相关的分子和免疫学事件，包括 HPV 特异性抗体的粘膜产生、活化的 T 和 NK 细胞的募集以及上皮完整性的破坏，也可能作为随后获得 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% 替诺福韦凝胶纳入计划生育诊所的可行性。具体来说我们 将： 1) 表征细胞和体液免疫反应，以及与 HPV 清除相关的生殖器上皮完整性水平； 2) 比较感染 HIV 的人与未感染 HIV 的人的 HPV 清除率的粘膜相关性。 HPV感染不会引起病毒血症；血清转化仅发生在约 60% 的个体中，即使如此，也仅发生在自然感染的晚期。尽管这些观察强调了了解生殖器 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，可以更好地了解 HPV 感染清除和 HIV 感染增强之间强大的流行病学关联的生物学基础。撒哈拉以南非洲地区 HPV 感染率高，加上 8-12 个月内的高 HPV 清除率，将加深我们对其对 HIV 感染的相对贡献的了解，并为设计适当的干预措施以降低 HIV 感染率提供信息。更好地了解清除生殖器 HPV 感染与 HIV 感染之间的关联对于解决更大的研究问题至关重要，这些问题包括 (1) 如何限制常见 HPV 感染对 HIV 的有害影响；(2) HPV 疫苗接种是否有可能影响 HIV 发病率，同时考虑到粘膜免疫反应随时间的变化、HPV 感染的数量和类型以及其他风险因素等复杂性。通过加强对支撑令人信服且一致的流行病学证据的生物机制的理解，我们可以开始确定并告知适当的、有针对性的和具体的艾滋病毒预防干预措施。