Impact of longitudinal CMV viremia on opportunistic neuroinfections in advanced HIV disease

Project Summary I am an Assistant Professor in the Division of Infectious Diseases & International Medicine at the University of Minnesota. My long-term goal is to become an independent investigator with expertise in conducting clinical trials with nested translational immunology research to further the management of AIDS-related opportunistic

infections of the central nervous system. I am particularly interested in developing the skillset, competence, and cultural rapport to conduct ethically-sound trials in resource-limited settings in Africa, where the burden of HIV/AIDS-related CNS infections disproportionately impacts the population.

Training: This K23 award will provide the mentoring, didactics, and hands-on training to establish an independent research career. With the mentorship of an interdisciplinary team with expertise in international clinical trials and immunology involving HIV-related opportunistic neuroinfections, I will: 1) Improve my

knowledge of biostatistical design and analysis, 2) Acquire experience on human immunology principles and data interpretation to facilitate effective translational research collaborations, and 3) Gain robust education and mentorship in clinical trial design and execution, particularly as it pertains to infectious diseases in Africa.

Research: CMV viremia is independently associated with mortality in persons with advanced HIV disease; however, no recommendations exist for the treatment or prevention of CMV viremia alone. My published data demonstrated CMV viremia increased the mortality hazard by 3-fold in a cohort with first-episode cryptococcal

meningitis. I hypothesize that CMV viremia exerts a mortality risk that is (1) time-dependent, and (2) associated with impairment of the host Th1 immune response (e.g. interferon-gamma [IFN-] response). My K23 objective is to build the skills and preliminary data necessary to design a future randomized clinical trial to test if anti-

CMV therapy might mitigate excess mortality. My K23 Specific Aims are: 1) Determine if CMV viremia is a time-dependent risk factor for 18-week mortality among Ugandans with advanced HIV disease and concomitant cryptococcal meningitis; and 2) Determine if host Th1 responses are impaired in persons with active CMV viremia compared to CMV non-

viremic persons among those with HIV-related cryptococcal meningitis. Deliverables: This study will provide key missing clinical trial design parameters, such as the optimal duration of an anti-CMV intervention (i.e. informed by CMV viremia duration/persistence and time-dependent mortality risk) and the appropriate risk criteria for enrollment (i.e. any baseline CMV viremia vs CD4-predicted

cumulative exposure). Further, identifying a plausible immune mechanism (e.g. impaired Th1 responses) opens the door for improved risk stratification and for future targeted immunomodulatory clinical trials (e.g. subcutaneous IFN-). A future randomized trial best determines if CMV viremia is a cause of excess mortality.