Immuno-Neuropathogenic mechanisms of HIV-1 clade B and C Infection

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DESCRIPTION (provided by applicant): Worldwide, approximately 33.3 million people are infected with human immunodeficiency virus type-1 (HIV-1). HIV-1 displays extraordinary genetic variations and the predominant subtype, clade B, is found in North America, Canada, Brazil, Western Europe and Australia whereas clade C is found specifically in Africa, Latin America, China, India and Nepal. Of these, clades B and C represent a large majority (>86%) of circulating HIV-1 variants and more than 56 % of the infection is with clade C. AIDS is often accompanied by immune and neuropathological abnormalities. Dopamine receptors (DRD) and transporter (DAT) are known to play a significant role in immuno-neuropathogenesis of HIV infection. Previous studies suggest that HIV-1 clade variations differentially induce the neuro-immunopathogenic mechanisms. We hypothesize that clade B and C infection exert differential effects on peripheral blood derived monocytes and central nerves system (CNS) cells leading to differential immuno-neuropathogenic effects and the mechanisms may be mediated by dysregulation of Ca2? dependent protein (CaMKs) kinases signaling pathways. Accordingly we will study (Aim #1) the effects of clade B and C virus infections on gene expression and protein modification of dopamine receptor-2 (DRD-2), dopamine transporter (DAT), rate limiting enzyme tyrosine hydroxylase (TH) and level of metabolite homovalinic acid (HVA) by monocytes and primary human CNS cells (astrocytes, neurons, microglial cells), and whether (Aim #2) the mechanism of differential dysregulation of DRD-2 and DAT is mediated by modulation of Ca2?dependent protein kinases (CaMKs) and cAMP response of element-binding protein (CREB) signaling pathways. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the impact of HIV subtypes influencing neuronal injury and which may help to develop therapeutic strategies for HIV-associated dementia and neurocognitive disorder.