Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

Abstract

Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/β-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit β-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to β-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of β-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of β-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect β-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.

Escalating morphine dosing in HIV-1 Tat transgenic mice with sustained Tat exposure reveals an allostatic shift in neuroinflammatory regulation accompanied by increased neuroprotective non-endocannabinoid lipid signaling molecules and amino acids

“…2 ). Although 2–14 days of morphine and Tat/HIV co-exposure typically exacerbates cytokine production, gliosis, and bystander neuronal injury in vitro [ 30 , 37 , 43 , 166 ] and in vivo [ 29 , 38 ], 3 months of Tat induction elicited a far less fulminant morphine-dependent interactive pathology. Morphine and Tat co-exposure elevated 3-NT in microglia, but failed to increase microglial numbers as seen previously following 48 h or 12-day Tat induction [ 29 , 31 ].…”

Priming Astrocytes With HIV-Induced Reactive Oxygen Species Enhances Their Trypanosoma cruzi Infection

“…In this context, neurological involvement is observed is the vast majority of HIV-coinfected patients (Ferreira et al, 1997;Cordova et al, 2008). Astrocytes have been proposed as parasite (Weinkauf et al, 2011;Silva et al, 2015Silva et al, , 2017, and also HIV target cells, as we and others have reported (Urquiza et al, 2017;Chen et al, 2020;Li et al, 2020;Proust et al, 2020).…”

Drugs of Abuse and Their Impact on Viral Pathogenesis

“…Additionally, Balinang et al also demonstrated increased HIV replication in neural progenitor cells in the presence of morphine [53]. Notably, HIV proteins also synergize with morphine to increase the expression of opioid receptors, alter cell cycle regulation, and exacerbate neurotoxicity and neuroinflammation [54][55][56][57][58][59][60].…”

“…Additionally, Balinang et al also demonstrated increased HIV replication in neural progenitor cells in the presence of morphine [53]. Notably, HIV proteins also synergize with morphine to increase the expression of opioid receptors, alter cell cycle regulation, and exacerbate neurotoxicity and neuroinflammation [54][55][56][57][58][59][60]. Using an in vitro HIV-CD4+ T cell system, Liang et al showed that morphine treatment induced more drug-resistant mutations under selective pressure from antiretroviral drugs and shortened the generation time for such mutations compared to controls treated with only antiretroviral drugs [61].…”