How HIV mediates central nervous system (CNS) damage is unknown. We are studying the pathogenesis of neurologic damage associated with HIV encephalitis, a known pathologic substrate of dementia. Early studies suggested the vast majority of HIV infected CNS cells were macrophages. With the advent of new technology (e.g. in situ PCR), this conclusion has been drawn in to question.
In Specific Aim #1 we will assess HIV CNS burden and compare measurements of virus to quantitative indices of gliosis and apoptosis.
In Specific Aim #2 we will use quantitative reverse transcriptase PCR to examine presence of an unconventional HIV CNS infection. We will explore the validity of the claim that many more CNS cells are infected with HIV and that infection of these cells is abortive (i.e. selective retroviral gene expression without productive infection). Thee studies will help define a role for selective HIV gene expression in the CNS. While many theories of neurodegeneration have focused on toxic effects of retroviral proteins and cytokines, in Specific Aim #3 we will explore the hypothesis that rather than presence of a toxin, loss of a trophic factor could account for neuropathology seen in HIV encephalitis. Recently there has been an explosion of trophic factors identified for the CNS. We will use quantitative reverse transcriptase PCR to screen for the expression of neurotrophic factor mRNA in l4 CNS regions of cases with and without HIV encephalitis. Trophic factors showing differences between HIV encephalitis and non-HIV encephalitis will be more specifically localized using in situ hybridization. Elucidation of the pathogenesis of neurodegeneration in HIV encephalitis will form the foundation of therapies directed at preventing or ameliorating this disease.
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