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: 10451546
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451546
• 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; 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.

虽然在一般人群中不常见，但患此病的风险显着增加（60-130 倍） HIV 感染者，尤其是男男性行为者 (MSM) 的肛门癌。肛门 癌症是由持续存在于肛门中的高危人乳头瘤病毒 (HR-HPV) 引起的 上皮。目前尚不清楚 HIV 感染是否会改变肛门微环境， 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 恶性肿瘤。 K07 的目标是进行微生物群方面的正式培训和指导， 粘膜免疫和致癌的分子生物学，并学习如何严格 通过分析整合这些成分来识别癌症预防标志物。因此，我们的 目标是：1）使用层次聚类来表征肛门微生物群的组成 一年后，通过持续检测到的 HR-HPV 来评估集群成员资格，以检测 HIV- 阴性和艾滋病毒阳性男性； 2) 从肛门拭子中确定局部细胞因子谱并评估 它们与持续性和非持续性 HR-HPV 的独立和中介关联 感染和未感染艾滋病毒的人； 3) 描述集群成员资格随时间的稳定性 这是否能区分艾滋病毒阴性和艾滋病毒阳性男性的持久性。达到 这些目标，我们建议使用存档的内容前瞻性地评估这些粘膜相互作用 来自正在进行的井中感染 HIV 和未感染 HIV 的 MSM 的肛门拭子样本 特征队列，尼日利亚的 TRUST/RV368 研究 (R01AI20913-01)。丽贝卡博士 Nowak 是一位杰出的候选人，他的研究重点是 HPV 的机制 HIV感染期间的转化。她的大部分研究起源于乌干达、津巴布韦、 和尼日利亚，这使她专注于全球癌症研究，这是该中心的优先事项之一 美国国家癌症研究所。 Nowak 博士得到了研究所的强有力的机构支持 马里兰大学医学院人类病毒学。她一定会保证 受保护的研究时间和丰富的资源，这将确保成功 过渡为独立资助的研究者。她稳健的培训计划包括：1）高 她的主要导师 Kevin Cullen 博士以及该领域的共同导师提供优质指导 微生物组学（Jacque Ravel 博士）、生物统计学（Soren Bentzen 博士）、粘膜免疫学（Dr. Soren Bentzen） 雷娜·费霍洛娃）； 2）基础免疫学课程，重点是粘膜； 3） 生物信息学培训； 4）多学科团队科学的经验。随着训练 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。

项目成果

Incidence and Clearance of Anal Human Papillomavirus Infection in 16 164 Individuals, According to Human Immunodeficiency Virus Status, Sex, and Male Sexuality: An International Pooled Analysis of 34 Longitudinal Studies.

根据人类免疫缺陷病毒状态、性别和男性性行为，16 164 名个体肛门人乳头瘤病毒感染的发病率和清除率：34 项纵向研究的国际汇总分析。

• 发表时间: 2023-02-08
• 作者: Wei, Feixue;Goodman, Marc T;Xia, Ningshao;Zhang, Jun;Giuliano, Anna R;D'Souza, Gypsyamber;Hessol, Nancy A;Schim van der Loeff, Maarten F;Dai, Jianghong;Neukam, Karin;de Pokomandy, Alexandra;Poynten, I Mary;Geskus, Ronald B;Burgos, Joaquin;Et
• 通讯作者: Et