Abstract In Sub-Saharan Africa, tuberculous meningitis (TBM) is the second most common cause of adult meningitis, and a major cause of morbidity and mortality among people living with HIV. While host immuno- deficiency clearly drives TBM pathogenesis, pathologic immune responses can also worsen disease. The key drivers of HIV-associated TBM pathogenesis remain undefined but likely differ from HIV-negative TBM, thus a study of the pathogenesis of TBM in HIV-infected humans is warranted and innovative. Opportunities for host-directed therapy in this vulnerable population remain unexplored. To optimize treatment of HIV/TBM and improve survival, it is critical to fully characterize host responses at the site of infection and identify immune signatures associated with good or poor outcomes. To this challenge, we bring our skills in experimental immunology of tuberculosis, matched with an experienced research team with a proven track record of clinical and translational research regarding AIDS-related meningitis in Uganda. Diagnosing TBM is notoriously difficult. The poor sensitivity (~50%) of standard methodologies detects only a subset of those with TBM, likely with the highest CSF bacillary burden. In these patients hypo-functional or pathologic immune responses, representing opposite extremes of immune function, may contribute to poor host control of infection. The higher sensitivity of Xpert Ultra enables semi-quantitative diagnosis of those with a lower burden of CSF bacteria and identifies a group with better immune control of the infection. Our preliminary data suggest that diagnosis with trace or very low Xpert Ultra is associated with better survival. In this project, we propose a new microbiologic/immunologic framework for understanding TBM, categorizing patients based on the differing Xpert Ultra PCR cycle-threshold, which serve as a surrogate for CSF bacterial burden. We seek to interrogate this framework by defining disease outcomes including survival and neurocognitive testing in these different framework groups, while correlating these findings with immunologic analyses of cellular immune responses in the CSF. Our central hypothesis is that CSF immune signatures correlate with key aspects of TBM disease pathogenesis including sensitivity of diagnostics, disease outcomes, and treatment responses. To test this, we will perform high parameter spectral flow cytometry and multiplex cytokine profiling of samples from the CSF and autopsy specimens of patients with HIV/TBM. By comparing these comprehensive immunologic data in groups of patients with either high or low CSF bacterial burden, in those with good or poor outcomes, and in the context of a clinical trial of standard vs high dose rifampin treatment, we aim to define the key contributions of host immunity to TBM pathogenesis. If our hypothesis is correct, the implications of this research are that immunomodulatory therapy will need to be customized to address the paucity or excess ...