PERSISTENT VIRUS ON CENTRAL NERVOUS SYSTEM IMMUNITY

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DESCRIPTION (from applicant's abstract): Human immunodeficiency virus-1 (HIV) infects the CNS during acute disease. However, the absence of an effective sterilizing immunity results in persistent CNS infection which may contribute to the progression of AIDS and the dementia complex (ADC). CD8+ T cells are the critical immune effectors which appear to control both acute and chronic infection. However, following the initial reduction in virus, CD8+ T cells are found within the CSF and are also associated with the lesions characteristic of AIDS encephalitis. The inability of CD8+ T cells to provide local CNS sterile immunity as well as their pathogenic potential are poorly understood. This proposal examines CD8+ T cell regulation within the unique immunological environment of the CNS. Aim 1 examines the hypothesis is that CD8+ T cell retention within the CNS following resolution of acute infection is driven by residual viral Ag. If our hypothesis is correct, only CD8+ T cells reactive to the persistent epitope will be persistently retained within the CNS. Aim 2 tests the hypothesis that CD8+ T cells recruited into the HIV+ CNS are derived from a pool that has not achieved a complete memory phenotype. If our hypothesis is correct, memory cells will be effective in clearing Ag, but will continue to express cytolytic activity even after CNS Ag expression is lost. This would suggest that the CD8+ T cells present in the HIV+ CNS, derived from naive precursors, may be functionally downregulated after CNS entry due to continued activation. Aim 3 tests the hypothesis is that CNS retained CD8+ T cells are not only defective in expression of cytolytic activity, are also defective in proliferation. These data will determine if the CD8+ T cells retained within the Ag+ CNS are in stasis providing a possible explanation for the absence of cytolytic activity and viral clearance. Aim 4 addresses four issues relative to Ag driven CNS recruitment of CD8+ T cells from the periphery: 1) is recruitment of activated C D 8+ T cells enhanced by CNS Ag; 2) does Ag plus focal inflammation influence recruitment of activated CD8+ T cells; 3) does CNS Ag influence recruitment of memory C D 8+ T cells; and 4) is recruitment of memory C D 8+ T cells increased when CNS Ag is associated with focal inflammation. Recipients include persistently infected mice (with different types of residual inflammation) and transgenic models in which Ag is expressed in either astrocytes only, parenchymal microglia only, a limited number of peripheral myelomonocytic cells (including perivascular microglia) and both astrocytes and peripheral myelomonocytic cells. Given the mixed phenotypes of PB L C D 8+ T cells HIV+ patients, these experiments will determine persistent Ag and/or focal inflammation influences on specifically recruiting C D 8+ T cell subsets. Our hypothesis is that recently activated CD8+ T cells are preferentially recruited by Ag associated with inflammation, thereby contributing to viral persistence. The use of transgenic mice will determine the role of Ag expressed within defined CNS cell types, in the presence and absence of peripheral Ag.