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

Thangavel Samikkannu, Kurapati V.K. Rao, Abdul Ajees Abdul Salam, Venkata S.R. Atluri, Elena M. Kaftanovskaya, Marisela Agudelo, Suray Perez, Changwon Yoo, Andrea D. Raymond, Hong Ding, Madhavan P.N. Nair

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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.

Original languageEnglish
Article number11130
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 09-06-2015

All Science Journal Classification (ASJC) codes

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    Samikkannu, T., Rao, K. V. K., Salam, A. A. A., Atluri, V. S. R., Kaftanovskaya, E. M., Agudelo, M., Perez, S., Yoo, C., Raymond, A. D., Ding, H., & Nair, M. P. N. (2015). HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity. Scientific Reports, 5, [11130]. https://doi.org/10.1038/srep11130