This proposal outlines clinical research studies that use the therapeutic strategy of structured antiretroviral treatment interruption (STI) to address both clinically practical and more fundamental pathogenetic issues centered on two interactive components of cerebrospinal fluid (CSF) in HIV infection: HIV, itself, and T lymphocytes. These studies use flow cytometry and molecular virological methods to explore the opposing hypotheses that the CSF pleocytosis developing during STI is either a concomitant of enhanced transitory-type infection triggered by changes in lymphocytes outside of the nervous system or is initiated by increase in autonomous-type infection within the CSF. These hypotheses and their corollaries will be examined through a series of studies addressing individual specific aims directed at defining: 1. The CSF virological and T lymphocyte changes and neurological sequelae of STI and their clinical implications; 2. the feasibility of using in vivo bromodeoxyuridine (BrDU) cell labeling to directly measure lymphocyte traffic into CSF; 3. the character of CSF lymphocytosis and its evolution through STI, including the functional phenotypes of trafficking cells; 4. CSF CD4 T lymphocyte HIV antigen reactivity using cytokine flow cytometry; 5. compartmentalization of CSF HIV infection using molecular methods during STI; 6. CSF CD4+ T lymphocyte infection; 7. the CSF chemotactic environment and its relevant principal components (through collaborative studies); 8. formal models of CSF virus and cell traffic and their principal components. We will also, 9., add well-characterized specimens to our CSF/ plasma bank for future studies. In the aggregate, these studies aim to provide novel information with important implications related to HIV treatment efficacy, pathogenesis of compartmentalized infection, virus-immune system interactions and CNS infection and its neurological consequences.
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