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

虽然在普通人群中并不常见，但有明显的(60-130倍)增加的风险 艾滋病毒感染者的肛门癌，特别是男男性行为者(MSM)。肛门 癌症是由持续存在于肛门的高危人类乳头瘤病毒(HR-HPV)引起的 上皮组织。目前尚不清楚艾滋病毒感染是否会改变肛门微环境， 特别是微生物区系和细胞因子，以增加持久性并最终促进坦率 恶毒。K07的目标是在微生物区系方面进行正式的培训和指导， 粘膜免疫和致癌的分子生物学，并学习如何严格 将这些成分进行分析整合，以确定癌症预防标志物。因此，我们的 目的是：1)使用层次聚类来表征肛门微生物区系的组成 并在一年后使用持续检测到的艾滋病毒HR-HPV评估集群成员- 阴性和HIV阳性的男性；2)从肛门拭子中确定局部细胞因子谱并评估 他们与持续性和非持续性HR-HPV的独立和中介关联 艾滋病毒携带者和非艾滋病毒携带者；以及3)描述集群成员随时间的稳定性以及 这是否区分艾滋病毒阴性和艾滋病毒阳性男性的持久性。要实现 这些目标，我们建议前瞻性地评估这些粘膜的相互作用 一口正在进行的井中HIV感染者和非HIV感染者的肛拭子样本 尼日利亚的TRUST/RV368研究(R01AI20913-01)。丽贝卡医生 诺瓦克是一位杰出的候选人，他的研究重点是人乳头瘤病毒的机制 在艾滋病毒感染过程中的转化。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。诺瓦克博士得到了麻省理工学院的强有力的机构支持 马里兰大学医学院的人类病毒学。她会保证 受保护的研究时间和对丰富资源的访问将确保成功 过渡到一名独立资助的调查员。她强有力的训练计划包括：1)高 她的主要导师凯文·卡伦博士以及该领域的联合导师提供了高质量的指导 微生物组(Jacque Ravel博士)、生物统计学(Soren Bentzen博士)、粘膜免疫学(Dr. Raina Fichorova)；2)基础免疫学课程，重点是粘膜；3) 生物信息学方面的培训；以及4)多学科团队科学的经验。通过培训 和经验，诺瓦克博士将准备寻求R01资金，以建立一个多学科 艾滋病毒感染过程中致癌病毒的研究计划。

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.