This is a revised five-year R01 grant application. A research team headed by Dr. Howard Fox with collaborators Steven Henriksen (electrophysiologist) and John Polich (bio-statistician) and research support staff from the Scripps Research Institute, La Jolla, CA has proposed to examine the relationship between virus levels and associated CNS disease in SIV-infected macaques. This group proposes to use an SIV-rhesus macaque model to test their hypothesis that CNS virus-associated pathology can be blocked, limited or reversed by the administration of antiviral drugs. Both mono-therapy (PMPA) and combination-therapy (PMPA and ZDV) will be used at various stages of infection. Further, the proposed research seeks to describe and determine the cause of CNS tissue damage associated with CNS dysfunction. CNS dysfunction will be detected by physiological monitoring during SIV infection. Their three Specific Aims will determine: 1.) Whether early antiviral treatment (two weeks PI) prevents or reduces the CNS pathology and whether termination of the treatment will result in the development of CNS symptoms and pathology, 2.) The histopathological characteristics of CNS pathology in treated and untreated SIV-infected macaques during a serial sacrifice experiment and 3.) Whether CNS abnormalities are reversible by lowering viral load in chronically infected macaques by initiating antiviral therapy at five months PI. A total of 44 Rhesus macaques will be used in the proposed experiments. All animals will be monitored by a well thought out series of assays and physiological assessments followed by detailed tissue analysis at necropsy.
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