GSK3β-activation is a point of convergence for HIV-1 and opiate-mediated interactive neurotoxicity

Abstract

Infection of the CNS with HIV-1 occurs rapidly after primary peripheral infection. HIV-1 can induce a wide range of neurological deficits, collectively known as HIV-1-associated neurocognitive disorders. Our previous work has shown that the selected neurotoxic effects induced by individual viral proteins, Tat and gp120, and by HIV+ supernatant are enhanced by co-exposure to morphine. This mimics co-morbid neurological effects observed in opiate-abusing HIV+ patients. Although there is a correlation between opiate drug abuse and progression of HIV-1-associated neurocognitive disorders, the mechanisms underlie interactions between HIV-1 and opiates remain obscure. Previous studies have shown that HIV-1 induces neurotoxic effects through abnormal activation of GSK3β. Interestingly, expression of GSK3β has shown to be elevated in brains of young opiate abusers indicating that GSK3β is also linked to neuropathology seen with opiate abusing patients. Thus, we hypothesize that GSK3β activation is a point of convergence for HIV- and opiate-mediated interactive neurotoxic effects. Neuronal cultures were treated with supernatant from HIV-1SF162-infected THP-1 cells, in the presence or absence of morphine and GSK3β inhibitors. Our results show that GSK3β inhibitors, including valproate and small molecule inhibitors, significantly reduce HIV-1-mediated neurotoxic outcomes, and also negate interactions with morphine that result in cell death, suggesting that GSK3β-activation is an important point of convergence and a potential therapeutic target for HIV- and opiate-mediated neurocognitive deficits.

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

“…; Masvekar et al . ). For all the experiments, vehicle refers to the diluent that is used to dissolve the drug.…”

“…; Masvekar et al . ). In brief, OLs were cultured in 12‐well plates and treated with Tat and GSK3β inhibitors.…”

“…, ; Masvekar et al . ). Dixon's two‐tailed test (95% confidence level) was utilized to identify and exclude outliers from analyses.…”

“…The sample sizes used here are commensurate with our a priori power analyses indicating large differences exceeding power = 0.80 detected between Tat− and Tat+ samples on Western blots of myelin basic protein (power = 1.00) and myelin‐associated glycoprotein (power = 0.89) using equivalent observations per group (Masvekar et al . ; Zou et al . ).…”

Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves μ-Opioid Receptors

“…HAND is specifically enhanced in the context of drug use, such as opiates, with worsening the consequences of HIV-1 in the central nervous system (CNS) (Bell et al, 1998; Arango et al, 2004; Anthony et al, 2005; Lan et al, 2015). Experimental models of acquired immune deficiency syndrome (AIDS) have further indicated an increase in virus and disease progression by opiates (Pérez-Casanova et al, 2007; Noel et al, 2008; Rivera-Amill et al, 2010; Bokhari et al, 2011; Hu et al, 2012; Masvekar et al, 2015). HIV-1 specifically targets subcortical and cortical areas of the brain, with HIV-1 positive individuals displaying deficits in sensorimotor function, executive function, learning and memory, and attention (Berger and Nath, 1997; Berger and Arendt, 2000; Heaton et al, 2011; Scott et al, 2011).…”