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.

Public Health Narrative: Anal cancer risk is increasing in men who have sex with men, dually infected with HIV and high-risk human papillomavirus (HR-HPV). Given their history of sexual intercourse, many of these men are ineligible for the HPV vaccines. The proposed study assesses the role of microbiota and cytokines in the anal mucosa on persistence of HR-HPV to identify immune pathways that may increase regression of precancerous lesions to prevent anal cancer.