Immuno-Neuropathogenic Mechanisms of HIV-1 clade B and C Grant

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

contributor

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