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.
Highlights
human immunodeficiency virus (HIV)-1 infection causes immune dysfunction and is a risk factor in the neuropathogenesis of brain disease[1]
The effect of METH combined with clade B gp[120] and METH with clade C gp[120] showed significant decrease in dopamine transporter (DAT) expression compared to either clade B gp[120] (p < 0 .05) or clade C gp[120] (p < 0 .001) alone (Fig. 2B). These results suggest that clade B and C gp[120] differentially regulate DRD-2 and DAT gene expression and these effects are potentiated when METH is combined with clade B gp[120] or clade C gp[120]
These results demonstrate that clade B gp[120] and METH significantly reduces DRD-2 protein levels compared to the untreated control whereas clade C gp[120] had no effect on DRD-2
Summary
HIV-1 infection causes immune dysfunction and is a risk factor in the neuropathogenesis of brain disease[1]. Previous studies demonstrated that the HIV-1 gp[120] and Tat proteins induce the over-stimulation of intracellular Ca2+16,17, which could affect the dopaminergic system and dysregulate CaMKs and CREB transcription in the CNS18,19. Studies demonstrated that methamphetamine (METH) users[20,21] and HIV-infected METH users have impaired immune function and synergistically potentiated neurotoxicity[22]. Despite mounting evidence that METH abuse potentiates HIV infection, mechanistic studies addressing the combined effects of METH and HIV infection on the dopaminergic system are lacking in patients with HIV-induced neuropathogenesis. We aim to elucidate the effect of HIV-1 clade B and C gp[120] on the dopaminergic system and the mechanisms by which METH potentiates neuronal impairments
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
