NEUROLOGICAL RESPONSE TO HAART

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The evidence is clear that highly active antiretroviral therapy (HAART) improves quality and quantity of life in HIV infected patients. There is growing but as yet poorly substantiated evidence that HAART also has a marked beneficial effect on the nervous system complications of HIV infection. There is little information on the exact mechanism of this nervous system improvement. We propose to evaluate a group of HIV infected (HIV+) subjects who are either HAART naive or have failed one regimen of HAART as indicated by an increase in systemic viral burden, and who are to be switched to another regimen. They will have indepth evaluation of nervous system function before starting or changing HAART, and then will be followed longitudinally to assess changes in nervous system function over time. Our premise is that, with HAART, nervous system function will improve in association with reduction of systemic and CSF viral load. We believe the improvement will be due to a down regulation of proinflammatory cytokine/chemokines in the nervous system, and this will be evidenced by a reduction in these compounds in the cerebrospinal fluid. Subjects will be clinically characterized through assessment of plasma and CSF HIV RNA viral load, neuropsychological, neurological, and psychological, including quality of life and adherence. We will complete viral characterization through genotyping, co-receptor type (CXCR4, CCR5), syncytia/nonsyncytial induction and assess these differences between virus in CSF and plasma. We will assess chemokines (MCP-1, MIP- 1alpha, SDF-1alpha), CNS inflammatory markers (TNFalpha, IL-6), and assay neurotoxicity (calcium influx imaging and cell death in neuronal cultures). To further aid in the determination of the relative effects of HAART on systemic and CNS viral load with failure, we will characterize and compare the virus populations in the CSF and plasma compartments.