HIV dementia remains an important manifestation of AIDS, developing in up to 15%. Despite highly active anti-retroviral therapy (HAART), the prosect that the brain might remain a sanctuary for HIV replication is real, and of great relevance for the effective long-term suppression of HIV infection. The Research Center will extend the observations that we have made during the last decade. The Research Center will refocus its questions in the context of the recent advances which have been made in our understanding of the biology of HIV infection and the therapy of HIV infection. The Research Center will investigate the mechanisms of neuronal damage and death. CNS, therapeutic responses to HAART, and the immunopathology and virology of HIV-associated dementia (""""""""AIDS dementia""""""""). HIV seropositive individuals will be studied prospectively to characterize the severity of neurological impairment. Individuals initiating HAART will have serial CSF analyses to study the acquisition of resistance mutations and to relate these to the durability of suppression of CSF HIV levels. The systematic clinical characterization of HIV-infected individuals through the Cores will provide the basis for detailed clinicopathological correlation in autopsy material using a variety of morphological methods, including assessment of the degree and cellular localization of cytokines and chemokines, and the state of activation of tissue macrophages. The mechanisms of monocyte entry into the CNS and regulation of cytokine and chemokine production will be examined in vitro. The importance of biological differences in brain HIV isolates from patients with and without dementia will be examined, with respect to their replicative capacity and ability to induce pro-inflammatory mediators. The role of the bone marrow in the aberrant production and processing of monocytes which potentially leads to increased CNS entry of activated or infected monocyte/macrophages will be explored. Finally, the mechanisms of neuronal injury and death, and the potential neurotoxic effects of viral proteins including gp41, will be examined. These studies will lead to an improved understanding of the pathophysiological mechanisms which lead to HIV dementia, and are likely to stimulate new avenues of therapy for HIV dementia. The studies of CSF viral load and resistance patterns will be directly relevant to the management of patients with established HIV dementia. The studies of CSF viral load and observations should lead to improvement sin the application of anti-retroviral and other therapies directed at the prevention or treatment of HIV dementia.
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