Role of anal microbiota, local cytokines and HIV in persistence of high-risk human papillomavirus

肛门微生物群、局部细胞因子和 HIV 在高危人乳头瘤病毒持续存在中的作用

• 批准号: 9979821
• 负责人: Rebecca G. Nowak
• 金额: $ 13.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979821
• 关键词: Age; Anaerobic Bacteria; Anal canal; Anus; Archives; Bioinformatics; Biometry; Cell physiology; Cervical; Cervix Uteri; Characteristics; Coitus; Data; Detection; Ensure; Environment; Enzymes; Epithelial; Epithelium; Funding; General Population; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV risk; HIV therapy; HPV-High Risk; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune Tolerance; Immunity; Immunology; Incidence; Individual; Infection; Institutes; Interdisciplinary Study; Intervention; Lead; Learning; Lesion; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of anus; Maryland; Mediating; Mentors; Mentorship; Modeling; Molecular Biology; Mucosal Immunity; Mucous Membrane; National Cancer Institute; Nigeria; Participant; Pathway interactions; Pattern; Population; Public Health; Recording of previous events; Research; Research Personnel; Research Proposals; Resources; Risk; Role; Sampling; Science; Squamous intraepithelial lesion; Swab; Time; Training; Uganda; Universities; Update; Uterine Lesion; Virus; Woman; Zimbabwe; anticancer research; antiretroviral therapy; cancer prevention; cancer risk; carcinogenesis; carcinogenicity; cohort; commensal bacteria; cytokine; experience; indexing; medical schools; men; men who have sex with men; microbial; microbiome; microbiome components; microbiota; multidisciplinary; preference; premalignant; prevent; programs; prospective; vaginal microbiome; virology

While uncommon in the general population, there is a marked (60-130 fold) increased risk of anal cancer in HIV-infected individuals, especially men who have sex with men (MSM). Anal cancer is caused by high-risk human papillomavirus (HR-HPV) that persists in the anal epithelium. It is currently not known whether HIV infection alters the anal micro environment, specifically the microbiota and cytokines, to increase persistence and eventually promote frank malignancy. The goals of the K07 are to undertake formal training and mentoring in microbiota, mucosal immunity, and molecular biology of carcinogenesis and to learn how to rigorously integrate these components analytically to identify cancer prevention markers. Therefore, our aims are to: 1) characterize the composition of the anal microbiota using hierarchical clustering and assess cluster membership with a persistently detected HR-HPV a year later for HIV- negative and HIV-positive men; 2) determine local cytokine profiles from anal swabs and assess their independent and mediating associations with persistent and non-persistent HR-HPV for those with and without HIV; and 3) describe the stability of cluster membership over time and whether that distinguishes persistence among HIV-negative and HIV-positive men. To achieve these aims, we propose to evaluate prospectively these mucosal interactions using archived anal swab samples from HIV-infected and HIV-uninfected MSM in an ongoing well characterized cohort, the TRUST/RV368 study in Nigeria (R01AI20913-01). Dr. Rebecca Nowak is an exceptional candidate whose research focuses on the mechanisms of HPV transformation during HIV infection. Much of her research has originated in Uganda, Zimbabwe, and Nigeria which has resulted in her focus on global cancer research, one of the priorities for the National Cancer Institute. Dr. Nowak has strong institutional support from the Institute of Human Virology at the University of Maryland School of Medicine. She will have guaranteed protected research time and access to a wealth of resources that will ensure a successful transition to an independently funded investigator. Her robust training plan includes: 1) high quality mentorship from her primary mentor, Dr. Kevin Cullen, as well as co-mentors in the field of microbiome (Dr. Jacque Ravel), biostatistics (Dr. Soren Bentzen), mucosal immunology (Dr. Raina Fichorova); 2) coursework in fundamental immunology with a focus on the mucosa; 3) training in bioinformatics; and 4) experience in multidisciplinary team science. With the training and experience, Dr. Nowak will be prepared to seek R01 funding to establish a multidisciplinary research program in carcinogenic viruses during HIV infection.

虽然普通人群罕见，但有明显的（60-130倍）的风险增加 艾滋病毒感染者，尤其是与男性发生性关系的男性（MSM）中的肛门癌。肛门 癌症是由持续存在于肛门的高风险人乳头瘤病毒（HR-HPV）引起的 上皮。目前尚不知道艾滋病毒感染是否改变了肛门微环境， 特别是微生物群和细胞因子，以增加持久性并最终促进坦率 恶性。 K07的目标是在微生物群中进行正规培训和指导， 粘膜免疫和致癌的分子生物学，并学习如何严格 分析这些组件以鉴定预防癌症标志物。因此，我们的 目的是：1）使用分层聚类来表征肛门菌群的组成 并评估群集成员资格，一年后持续检测到HR-HPV的HIV- 负面和艾滋病毒阳性男性； 2）确定肛门拭子的局部细胞因子谱并评估 他们与持久和非持久性HR-HPV的独立和中介协会 患有和没有艾滋病毒的人； 3）描述群集会员随着时间的稳定性和 这是否区分了艾滋病毒阴性和艾滋病毒阳性男性的持久性。实现 这些目的，我们建议使用存档的这些粘膜相互作用进行前瞻性评估 来自HIV感染和HIV未感染的MSM的肛门拭子样品在正在进行的井中 在尼日利亚的Trust/RV368研究（R01AI20913-01）的特征。丽贝卡博士 诺瓦克（Nowak）是一个杰出的候选人，其研究重点是HPV的机制 HIV感染期间的转化。她的许多研究起源于津巴布韦的乌干达 和尼日利亚导致她专注于全球癌症研究，这是 国家癌症研究所。诺瓦克博士得到了研究所的大力机构支持 马里兰大学医学院的人类病毒学。她会保证 受保护的研究时间并获得大量资源，以确保成功 过渡到一位独立资助的研究者。她强大的培训计划包括：1）高 她的主要导师凯文·库伦（Kevin Cullen）博士以及该领域的授权指导 Microbiome（Jacque Ravel博士），生物统计学（Soren Bentzen博士），粘膜免疫学（博士 Raina Fichorova）; 2）基本免疫学课程工作，重点是粘膜； 3） 生物信息学培训； 4）在多学科团队科学方面的经验。在培训中 和经验，Nowak博士将准备寻求R01资金来建立多学科 HIV感染期间致癌病毒的研究计划。