Cocaine, the second highest used illegal drug in the US, reduces CNS immune responses to HIV-1, increasing
the severity and onset of HIV-1-mediated neurotoxicity. 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 (33);
however, uncontrolled inflammation and the failure to control HIV-1 replication is a continued problem.
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 triggering
inflammatory and antiviral signaling in cocaine and HIV-1. Cocaine exposure in astrocytes, increases
interferons (IFNs) (33) and activity of the IFN stimulated response element (ISRE), presumably via MAVS. We
identified that cocaine induced mitochondrial toxicity, which regulates MAVS function and AIM2 inflammasome
activation (30, 77). We discovered that cocaine exposure in astrocytes is a major regulator of AIM2 priming
measured by increased caspase-1 cleavage and AIM2 levels, an IFN stimulated gene (ISG) (32, 88).
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 NF¿B signaling and IFN production (16, 23). We established that repeated cocaine exposure reduced
MAVS cleaved products and increased MAVS aggregation, which differentially dictate IFN and NF¿B signaling,
and we measured increased cytokines/chemokines and decreased IFNß. 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 (35). ASC is regulated by kinases initiated by
MAVS and IFN signaling (36, 37) 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. To test this hypothesis we will uncover mechanisms by which cocaine cause AIM2
inflammasome priming via astrocyte MAVS activation (Aim 1); delineate astrocyte MAVS and AIM2 scaffolding
and crosstalk on AIM2 inflammasome oligomerization and signaling (Aim 2); and explore the impact of
astrocyte ASC regulation/recruitment in AIM2 signaling and attenuated MAVS activation in cocaine and HIV-1.
Repeated cocaine exposure, and/or subsequent introduction of HIV-1, inundates the innate immune response
producing a hyperimmuno and decreased antiviral phenotype, increasing the risk of HIV-1 neurotoxicity.