HIV encephalopathy, a generic name for a variety of neurological, cognitive, and affective disorders associated with HIV infection, afflicts at least 50% of AIDS patients to varying degrees. HIV encephalopathy can be divided into subacute chronic encephalitis and the AIDS dementia complex (ADC). The pathogenesis of ADC which remains a very enigmatic process which may involve both direct mechanisms in which highly restricted infections of glial or neuronal cells exhibit altered function, or indirect mechanisms in which either HIV proteins or products of HIV-infected microglia exert toxic effects on glial and/or neurons leading to neural dysfunction. The present application is directed toward several aspects of the pathogenesis of ADC. Gonzalez-Scarano's project: HIV infection of cultured neural cells will use primary cultures of uninfected adult human brain to prepare microglia, astroglia, and oligodendroglia cultures to investigate (i) which HIV strains replicate in microglia and whether microglia-tropism can be distinguished from macrophage tropism; (ii) whether cultured oligodendroglia can be infected using sensitive methods to detect highly restricted infection. (iiib) A human teratocarcinoma cell line (N-Tera 2) which can be differentiated into mature neurons will be used to determine whether HIV will produce a highly restricted infection; and (iiib) whether the products of infected microglia will exert a """"""""toxic"""""""" effect on N tera 2-derived neurons. Wigdahl's Project: HIV LTR and viral gene expression in the human nervous system will use primary cultures of fetal human neural cells to study the determinants of HIV replication in glial cells, particularly astroglia, with particular attention to the role of the long terminal repeat (LTR) as a regulator of HIV genome expression. Collman's Project: Genetics of neuropathic HIV variants will focus on HIV genetic determinants of neurotropism, with particular attention to microglia- tropism, using chimeric viruses constructed from infectious cDNA clones with different biological properties. The Molecular virology core will provide state-of-the-art support for detection of HIV replication with focus on in situ polymerase chain reaction (PCR) methodology. The Neuropathology core is a tissue core which will provide optimally obtained and stored samples from brains of patients dying of AIDS with varying degrees of CNS involvement, and will also conduct studies of the cellular localization of HIV genomes and proteins in infected human brains.
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