This application proposes to establish an international, multi-centered consortium with sites in Goteborg Sweden, Milan Italy, San Francisco USA, and Sydney Australia to advance the rational use of cerebrospinal fluid (CSF) molecular markers to manage (prevent, diagnose and treat) and understand the pathogenesis of HIV-1 brain infection and its major clinical consequence, the AIDS dementia complex (ADC). The requested funding will be used to: 1. Develop the infrastructure, methodologies and procedures of the cooperative consortium that facilitate a sequential, more expeditious approach to analysis of CSF changes in HIV infection that could be accomplished by a single institution; 2. Carry out initial screening of a preliminary group of candidate CSF markers, with components assessing virological, host immunological, neural and blood-brain barrier contributions to CSF composition, and to reduce this to a smaller initial core CSF marker battery using a matrix of about 160 well-defined, cross-sectional CSF and blood sample pairs; 3. Further assess and refine this battery into a well-characterized secondary core CSF marker battery by additional (a) cross-sectional study to test the diagnostic value of the individual and combined markers with a more complex, real-world spectrum of samples and patients and (b) short-term longitudinal studies of marker dynamics after initiation of cessation of anti-retroviral therapy; 4. Continue to enlarge to enlarge CSF/plasma sample repositories and to assess additional markers as candidates to add to or replace component markers of the secondary battery and to address questions of pathogenesis; 5. Develop formal models of individual marker dynamics and their interactions; 6. Use the information derived from these studies to formulate a set of CSF marker guidelines for the design of clinical trials. Additionally, throughout the 5 years of this study, measures will be taken to prepare for and subsequently extend this study through integration with studies using other modalities, including functional neuroimaging and genetic analyses.
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