title: HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity.
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.
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Thangavel
authors.initials: T
authors.lastname: Samikkannu
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Kurapati V K
authors.initials: KVK
authors.lastname: Rao
authors.affiliation: Department of Atomic and Molecular Physics, Manipal University, Manipal 576104, Karnataka, India.
authors.forename: Abdul Ajees Abdul
authors.initials: AAA
authors.lastname: Salam
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Venkata S R
authors.initials: VSR
authors.lastname: Atluri
authors.affiliation: Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Kaftanovskaya
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Marisela
authors.initials: M
authors.lastname: Agudelo
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Suray
authors.initials: S
authors.lastname: Perez
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Florida International University, Miami, Florida 33199.
authors.forename: Changwon
authors.initials: C
authors.lastname: Yoo
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Raymond
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
authors.forename: Madhavan P N
authors.initials: MPN
authors.lastname: Nair
mesh_terms: D000595:Amino Acid Sequence; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000145:classification*; D006801:Humans; D008694:Methamphetamine / Q000378:metabolism* / Q000633:toxicity; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4