The pathogenesis of HIV encephalopathy is obscure, since HIV replication in the CNS is minimal and the cells most permissive for HIV are macrophages rather than neurons or glial. We propose to study the pathogenesis of HIV encephalopathy. I. HIV INFECTION OF CULTURED HUMAN NEURAL CELLS compares the level of replication in different glial and neural lines, most of which develop a persistent latent infection. Latent infection will be analysed to determine (a) the viral entry pathway which is probably not CD4; (b) the mechanism of viral latency; (c) the mechanism of viral activation and virus rescue after induction and cocultivation. II. HIV MEDIATED DAMAGE AND CD4 IN CULTURED HUMAN FETAL NEURAL TISSUES. Cultured human fetal neural cells are susceptible to HIV infection. (a) This project will explore the entry step in infection by determining the distribution and characterization of CD4 and CD4-related molecules (RNA and protein) in cultures of human fetal nervous system. (b) As part of Project IV, the toxic or trophic effect of products of HIV-infected monocytes will be tested. III. HIV INFECTION OF CULTURED HUMAN MONOCYTES. The role of monocyte infection in HIV encephalopathy will be studied (a) by comparison of replication patterns of monocyte-tropic variants with standard T lymphocyte-tropic variants of HIV; (b) by cloning, sequencing, and construction of recombinants between M-tropic and T-tropic variants; and (c) by preparing supernates from monocytes with productive or latent infections which will be tested (Project IV) for their toxic or trophic effects on cultured human neural/glial cells. IV. MECHANISMS OF HIV NEUROTOXICITY. To explore possible mechanisms by which HIV infection might produce neurotoxicity, we propose to (a) use cultures of rat CNS and PNS to assay for toxic effects of products of infected or uninfected human monocytes; (b) to identify the toxic products by fractionation of monocyte supernates; (c) to test affected cells for deficits in their biophysical, biochemical, or surface antigen integrity; and (d) in collaboration with Project II, to test macrophage products for neurotoxicity in cultures of human fetal neural cells.
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