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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
Cook, Denise R; Gleichman, Amy J; Cross, Stephanie A et al. (2011) NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury. J Neurochem 118:1113-23
Gannon, Patrick; Khan, Muhammad Z; Kolson, Dennis L (2011) Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol 24:275-83
Loftin, Lamorris M; Kienzle, Martha; Yi, Yanjie et al. (2011) R5X4 HIV-1 coreceptor use in primary target cells: implications for coreceptor entry blocking strategies. J Transl Med 9 Suppl 1:S3
Cross, Stephanie A; Cook, Denise R; Chi, Anthony W S et al. (2011) Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection. J Immunol 187:5015-25
White, Michael G; Wang, Ying; Akay, Cagla et al. (2011) Parallel high throughput neuronal toxicity assays demonstrate uncoupling between loss of mitochondrial membrane potential and neuronal damage in a model of HIV-induced neurodegeneration. Neurosci Res 70:220-9
Loftin, Lamorris M; Kienzle, Martha F; Yi, Yanjie et al. (2010) Constrained use of CCR5 on CD4+ lymphocytes by R5X4 HIV-1: efficiency of Env-CCR5 interactions and low CCR5 expression determine a range of restricted CCR5-mediated entry. Virology 402:135-48
Cheung, Ricky; Malik, Mobeen; Ravyn, Vipa et al. (2009) An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. J Leukoc Biol 86:833-45
Yadav, Anjana; Collman, Ronald G (2009) CNS inflammation and macrophage/microglial biology associated with HIV-1 infection. J Neuroimmune Pharmacol 4:430-47

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