The candidate's long-term goal is to understand, then prevent or treat, mechanisms underlying the damaging effects of HIV in the central nervous system (CNS). The proposed research focuses upon events in the CNS during primary HIV infection, defined as the first six months after initial acquisition of virus. HIV enters the CNS in the earliest stages of infection, and during chronic infection the CNS is a site of persistent viral infection. The underlying hypothesis of the proposal is that early neuroinvasion by HIV involves viral trafficking in the setting of host immune activation and allows the establishment of persistent and compartmentalized CNS infection. The candidate will use serial cross-sectional evaluations of individuals during primary infection and during initiation and interruption of therapy to longitudinally define CNS host responses and features of cerebrospinal fluid (CSF) HIV populations.
The first aim i s to demonstrate the natural history of host CNS responses of immune activation, inflammation and tissue injury through measurement of cerebral metabolites by high-field (4 Tesla) magnetic resonance spectroscopy, CSF cellular and inflammatory changes, and neurobehavioral indices.
The second aim i s to compare viral loads and molecular characteristics of viral populations between the CSF and plasma, including genotypic and phenotypic resistance, chemokine receptor utilization, and clonal analysis, to demonstrate early establishment of compartmentalized infection.
The final aim i s to use the above techniques to define the effects of treatment with antiretroviral therapy on the course of primary HIV in the CNS, through cross-sectional, serial studies of individuals initiating treatment for reasons independent of this proposal. Identification of primary HIV infection as a crucial period for establishment of CNS infection and injury and revealing the early effects of treatment in the CNS will profoundly influence treatment strategies in early HIV. The candidate's career development plan will allow her to translate observations from clinical research into improved understanding and treatment of CNS complications of HIV. Participation in a formal Advanced Training in Clinical Research program will foster sophisticated and responsible investigation. Clinical service in neurology will include care of patients with AIDS as well as those with other infectious conditions. Finally, the guidance of Drs. Price, Meyerhoff, and Hecht and support from UCSF's Neurology Department will allow the applicant to excel as an integral member of the academic community. ? ?
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