Immuno-Neuropathogenic Mechanisms of HIV-1 clade B and C Grant
Overview
abstract
- 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.
date/time interval
- January 12, 2012 - December 31, 2014
awarded by
sponsor award ID
- 1R03MH096640-01
local award ID
- AWD000000002114
Affiliation
contributor
- Thangavel, Samikkannu Principal Investigator 2012 - 2014
Research
keywords
- AIDS Dementia Complex
- Acids
- Acquired Immunodeficiency Syndrome
- Affect
- Africa
- Astrocytes
- Attention
- Attenuated
- Brazil
- Ca(2+)-Calmodulin Dependent Protein Kinase
- Calcium/calmodulin-dependent protein kinase
- Canada
- Cells
- China
- Clinical
- Cyclic AMP-Responsive DNA-Binding Protein
- Development
- Disease
- Dopamine Receptor
- Enzymes
- Functional disorder
- Gene Expression
- Gene Proteins
- Genetic Variation
- HIV
- HIV Envelope Protein gp120
- HIV Infections
- HIV-1
- Homovanillic Acid
- Human
- Immune
- Incidence
- India
- Infection
- Latin America
- Lead
- Life
- Mediating
- Microglia
- Nepal
- Nerve
- Neurocognitive
- Neuronal Injury
- Neurons
- Neuropathogenesis
- North America
- Patients
- Pharmaceutical Preparations
- Phosphotransferases
- Play
- Post-Translational Protein Processing
- Protein Kinase
- Proteins
- Role
- Short-Term Memory
- Signal Pathway
- System
- Therapeutic
- Tyrosine 3-Monooxygenase
- Variant
- Virus
- Virus Diseases
- Western Australia
- Western Europe
- dopamine transporter
- global health
- monocyte
- peripheral blood
- prevent