HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity

Sci Rep. 2015 Jun 9;5:11130. doi: 10.1038/srep11130.

Abstract

HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, α -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Cells, Cultured
  • Dopamine Agonists / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / classification*
  • Humans
  • Methamphetamine / metabolism*
  • Methamphetamine / toxicity
  • Molecular Sequence Data
  • Neurons / drug effects*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Sequence Homology, Amino Acid

Substances

  • Dopamine Agonists
  • Enzyme Inhibitors
  • HIV Envelope Protein gp120
  • Receptors, Dopamine D2
  • Methamphetamine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4