Role of the NLRP3 Inflammasome in Mediating Microglial Activation and Development of Neuropsychiatric Symptoms Induced by HIV, Antiretrovirals and Cocaine

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Abstract Although people living with HIV (PLWHIV) have comparable life-expectancy as the HIV-negative population does, their life-quality is still deeply compromised due to the prevalence of neuropsychiatric disorders including depression and anxiety. The main pathological changes in the brains of those people include aberrant microglial (Mg) activation and neuronal injuries. Drug abuse is a high comorbidity of HIV infection and abused drugs could exaggerate the existing neurologic complications in PLWHIV. The detailed mechanisms underlying such phenomenon remain much elusive. Several contributing factors have been suggested for such neurological disorders including the continued expression HIV proteins such as trans-activator of transcription (TAT), the long-term use of antiretrovirals (ARVs), and drugs of abuse. Our preliminary data demonstrated that :1) NLRP3 inflammasome signaling was involved in HIV-TAT-mediated Mg activation; 2) cocaine activated Mg through dysregulating miR-124/TLR4 axis, which could be reversed by inhibition of NLRP3 inflammasome; 3) combination ARVs used in clinical practice (tenofovir:TFV, emtricitabine:FTC, and dolutegravir:DTG) could activate Mg via lysosomal dysfunction; 4) co-exposure of Mg to three agents (TAT, cocaine, and ARVs) intriguingly resulted in increased activity of NLRP3 inflammasome in vitro; 5) IL1β, the final executor of NLRP3 inflammasome activation, decreased the spine density and increase the glutamate receptor ionotropic NMDA subunits (Grins) in vitro; and 6) increased NLRP3 inflammasome activity was shown in the brains of SIV-infected macaque. Based on these findings and two distinct steps of NLRP3 inflammasome activation, we hypothesize that exacerbated NLRP3 inflammasome activation in the context of HIV-TAT/HIV, cocaine, ARVs will lead to exaggerated Mg activation and neuronal injuries, which are responsible for the high incidence of neuropsychiatric disorders in PLWHIV with cocaine use. We will test this hypothesis in the following two specific aims (SA) using complimentary in vitro and in vivo approaches. SA1: Investigate the role of NLRP3 inflammasome in Mg activation and neuronal injuries in the context of HIV-TAT/HIV, cocaine, & ARVs. We will split this SA into three sub aims. SA1A will explore the detailed mechanisms responsible for exaggerated NLRP3 inflammasome activation in vitro; SA1B will explore the mechanisms underlying NLRP3 inflammasome-mediated neuronal injuries; and SA1C will investigate the status of NLRP3 inflammasome and neuronal injuries in archived SIV- infected macaque brains and HIV-infected individuas with or without cocaine use. SA2: Explore the potential therapeutic effects of NLRP3 inflammasome inhibition on neuropsychiatric behaviors in HIV iTat mice in vivo.