ABSTRACT/SUMMARY Approximately 37 million people worldwide are living with HIV/AIDS. No cure for HIV exists and infected patients must remain on antiviral therapy for life. The inability of current HIV treatment to eradicate HIV infection has been attributed to the establishment of viral “reservoirs”, infected cells or tissues unresponsive to antiviral therapy. Similarly, approximately 50% of AIDS-related deaths are due to Cryptococcus or Mycobacterium tuberculosis (TB) infection that is recalcitrant to antifungal or anti-TB treatment, particularly for central nervous system (CNS) disease where “reservoirs” of cells are either resistant to or not exposed to adequate anti-infective therapy. The CNS is believed to be a significant reservoir for these pathogens; however, current understanding of drug penetration into the CNS is limited, based on cerebrospinal fluid (CSF) concentrations. However, CSF is not brain tissue. Herein we propose utilization of tissues collected postmortem from HIV-infected Ugandan subjects with and without infectious meningitis. We propose to add detailed pharmacologic studies onto ongoing clinical trials. Our long-term objective is to optimize therapy of HIV and opportunistic infections to reduce overall mortality. To meet our objective, we aim to 1) localize and quantify antiretroviral distribution within and across compartments within the CNS; 2) localize and quantify distribution of anti-infective agents (anti-fungal and anti-TB) within and across CNS compartments, and 3) in collaboration with intramural NIH, determine if reduced levels of antiretrovirals in CNS tissue are associated with increased HIV RNA and/or DNA. Analysis of these post-mortem tissues provides a unique opportunity to study important events in tissue sites, such as brain, that are difficult to access in living subjects. This project builds on existing collaboration and research infrastructure between Makerere University and University of Minnesota. This project represents a unique synergy between existing strengths of the co-PIs. Dr. Robert Lukande is an experienced pathologist who can provide expertise in the performance and interpretation of autopsies while Dr. Melanie Nicol has advanced training in clinical pharmacology and performing drug distribution studies. These findings are expected to further inform the limitations of CSF as a surrogate for overall CNS drug exposure and will inform future drug development and use, so as to improve neurologic outcomes for patients infected with HIV. Curative strategies to eradicate HIV reservoirs in the CNS can also be explored.

PROJECT NARRATIVE It is unknown whether drugs being used to treat HIV and HIV-related infectious meningitis are able to adequately reach areas of the brain where these pathogens reside. In this project, we will use brain tissues collected during autopsy from individuals who pass away while receiving anti-HIV, antifungal, or anti- tuberculosis therapy to quantify and localize drug exposure within the brain. Findings will be used to improve therapies and develop curative strategies for HIV and infectious meningitis.