Cocaine reduces CNS immune responses to HIV-1. Astrocytes are the first line of defense against toxicity in the CNS and initiate inflammatory responses to HIV-1 and antiviral activity following cocaine exposure; however, uncontrolled inflammation
and the failure to control HIV-1 replication is a continued problem. Pattern recognition receptors (PRRs), such as mitochondrial antiviral signaling protein (MAVS), together with absent in melanoma 2 (AIM2)-like receptor inflammasomes, their interactions,
crosstalk and dual scaffolding could be key mechanisms in triggering inflammatory and antiviral signaling in cocaine and HIV-1.
Cocaine exposure in astrocytes, increases interferons (IFNs) and activity of the IFN stimulated response element (ISRE), presumably via MAVS. We identified that cocaine induces & mitochondrial toxicity, which regulates MAVS function and AIM2 inflammasome
activation. We measured increased caspase-1 cleavage with HIV-1 and identify that cocaine exposure in astrocytes is a major regulator of AIM2 priming measured by increased AIM2 levels, an IFN stimulated gene (ISG). Furthermore, MAVS plays a crucial
role in cocaine induced AIM2 priming as demonstrated in MAVS downregulated astrocytes.
Dual overactivation of MAVS and AIM2 produce chronic inflammatory pathologies, via NFκB signaling and IFN production. We established that repeated cocaine exposure reduced MAVS cleaved products and increased MAVS aggregation, which differentially
dictate IFN and NFκB signaling, and we measured increased cytokines/chemokines and decreased IFNβ. Interestingly, AIM2 binding partner, adaptor associated speck-like protein (ASC), binds MAVS via caspase recruitment domain (CARD)-
CARD homotypic interactions to inhibit MAVS-induced IFN generation. ASC is regulated by kinases initiated by MAVS and IFN signaling and may play a vital role in promoting AIM2-induced aberrant neuroinflammation and reduced MAVS antiviral signaling,
in cocaine and HIV-1.
We hypothesize that cocaine promotes MAVS activation via mitochondrial toxicity, priming AIM2 inflammasomes. Repeated cocaine exposure, and/or HIV-1, results in dual recruitment of ASC to astrocyte MAVS/AIM2. ASC recruitment initiates signal transduction
events triggering astrocyte-induced inflammation and decrease antiviral signaling, promoting astrocyte-induced neurotoxicity in cocaine and HIV-1.