Cocaine evokes a profile of oxidative stress and impacts innate antiviral response pathways in astrocytes

Abstract

HIV-1 and Zika virus (ZIKV) represent RNA viruses with neurotropic characteristics. Infected individuals suffer neurocognitive disorders aggravated by environmental toxins, including drugs of abuse such as cocaine, exacerbating HIV-associated neurocognitive disorders through a combination of astrogliosis, oxidative stress and innate immune signaling; however, little is known about how cocaine impacts the progression of ZIKV neural perturbations. Impaired innate immune signaling is characterized by weakened antiviral activation of interferon signaling and alterations in inflammatory signaling, factors contributing to cognitive sequela associated with cocaine in HIV-1/ZIKV infection. We employed cellular/molecular biology techniques to test if cocaine suppresses the efficacy of astrocytes to initiate a Type 1 interferon response to HIV-1/ZIKV, in vitro. We found cocaine activated antiviral signaling pathways and type I interferon in the absence of inflammation. Cocaine pre-exposure suppressed antiviral responses to HIV-1/ZIKV, triggering antiviral signaling and phosphorylation of interferon regulatory transcription factor 3 to stimulate type I interferon gene transcription. Our data indicate that oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immune responses. Although astrocyte antiviral signaling is activated following detection of foreign pathogenic material, oxidative stress and increased cytosolic double-stranded DNA (dsDNA) can drive antiviral signaling via stimulation of pattern recognition receptors. Pretreatment with the glial modulators propentofylline (PPF) or pioglitazone (PIO) reversed cocaine-mediated attenuation of astrocyte responses to HIV-1/ZIKV. Both PPF/PIO protected against cocaine-mediated generation of reactive oxygen species (ROS), increased dsDNA, antiviral signaling pathways and increased type I interferon, indicating that cocaine induces astrocyte type I interferon signaling in the absence of virus and oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immunity. Lastly, PPF and PIO have therapeutic potential to ameliorate cocaine-mediated dysregulation of astrocyte antiviral immunity possibly via a myriad of protective actions including decreases in reactive phenotype and damaging immune factors.

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorders

“…The current study extends these findings by identifying transcriptional deregulation in MND, specifically C/EBPβ and linking its targets to marker genes in astroglia. This may be particularly important as astroglia have been recently implicated in metabolic complications of HAND and AD [48][49][50][51][52][53]. Also consistent with the findings presented here, a recent study showed that YKL-40, a biomarker that reflects astroglial activation, is upregulated in cerebrospinal fluid from HAD cases and is associated with axonal injury [54].…”

Transcriptomic analysis of brain tissues identifies a role for CCAAT enhancer binding protein β in HIV-associated neurocognitive disorder

“…The current study extends these findings by identifying transcriptional deregulation in MND, specifically C/EBPβ and linking its targets to marker genes in astroglia. This may be particularly important as astroglia have been recently implicated in metabolic complications of HAND and AD [49][50][51][52][53][54]. Also, consistent with the findings presented here, a recent study showed that YKL-40, a biomarker that reflects astroglial activation, is upregulated in cerebrospinal fluid from HAD cases and is associated with axonal injury [39].…”

Nucleic acid oxidation is associated with biomarkers of neurodegeneration in CSF in people with HIV

“…HIV proteins and ARVs can damage mitochondria, which can generate reactive oxygen species (ROS). 4 , 16 – 18 HIV proteins can also induce ROS generation as part of the inflammatory response. 19 Thus, persistent low-level HIV protein expression or chronic exposure to ARV likely contributes to long-term exposure to ROS.…”

“…HIV proteins and ARV can induce mitochondria to generate ROS as part of the inflammatory response. 17 Recent studies show that astrogliosis and inflammation in AD and in PWH may compromise mitochondrial homeostasis in neurons leading to neurodegeneration, perpetuating ROS-induced inflammation and neurodegeneration. 18 Strategies that disrupt the cycle between oxidative stress, neuroinflammation, and neurodegeneration may be useful in slowing the aging process in PWH on ARVs.…”