The experiments proposed here are designed to address the relationship between the virus, the host's response to virus, and alterations in CNS functions. We will focus on testing the hypothesis that there is a CTL response in the CNS that serves to help control viral load, but at the cost of damage to the CNS. First, we will investigate the nature and extent of the early CTL response to SIV infection in the CNS. We will asses whether there is a regional specificity of SIV infection or CTL response in the brain. Examination of measures of oxidative stress, a common potential mechanism for many dementing conditions, will assess the potential for these CTL and other events occurring in the host/viral interaction to induce damage to the CNS. Additionally, control of CTL migration by chemokines produced by the infected CNS will be investigated. Second, we will assess the nature of the CTL response in the CNS over time, compare it to the CTL response occurring in the periphery, and relate these findings to the development of CNS functional abnormalities. In order to test whether the level of peripheral viral load plays a role in the maintenance of a CNS immune response, one group of animals will receive anti-viral treatment at two weeks post-viral inoculation, at the peak of peripheral viral load and CTL response. The potential for diminution of the CNS CTL response, versus a perpetuation, will be analyzed to determine the relationship of CNS CTL to peripheral viral load, and their joint relationship to CNS dysfunction and pathology. This will aid in the examination of whether the viral-immune interactions in the CNS compartment can occur independently of those in the blood and lymphoid tissue. Third, we will examine the clonality of CTL responses in the CNS during the acute and chronic infection to assess whether the CNS response is representative of the immune response in the peripheral compartment or whether evidence of local, possibly clonal or oligoclonal amplification occurs within the CNS. We will also use anti-viral therapy and its withdrawal to model the development of viral resistance or failure of effective therapy, and determine the vulnerability of the CNS to re-infection in this setting, and the role CNS CTL play in the response to the rebound viremia.
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