The impact of cannabis use on the inflammasome in people with HIV

About This Grant

Project Summary Compared to HIV seronegative persons, people with HIV (PWH) suffer from increased rates of comorbidities, including HIV-associated neurocognitive impairment (NCI). These HIV-associated comorbidities are driven, in part, by chronic inflammation and immune cell dysfunction. The drivers of this inflammation and exact mechanisms remain unknown. However, the inflammasome is increasingly recognized as an important mediator of the innate immune response and a driver of comorbid diseases via accelerated aging termed “inflammaging”. Indeed, HIV itself has been described as an accelerated aging process possibly mediated via its associated chronic inflammation. Supporting this theory are studies which have demonstrated that HIV proteins and nucleic acids can activate the NLRP3 inflammasome and IL-1β production in immune cells. However, co-existing comorbidities, such as drug use, are also immunomodulatory and introduce confounding immunological effects that make the study of inflammasome activation in PWH difficult. Importantly, cannabis use is highly prevalent among PWH, and increasing evidence suggests cannabis has important immunomodulatory effects. However, the strength and directionality of cannabinoid modulation of the inflammasome in PWH remains and its impact on HIV-associated comorbidities, such as NCI, remain largely unknown. To address this challenge, this proposal will determine the impact of recreational cannabis use on the NLRP3 inflammasome in PWH leveraging biospecimens from a unique cohort of clinically and neurologically phenotyped HIV-infected CB users and non-users. We have recently found that, compared to non-users and cannabis/tobacco dual users, cannabis users exhibit distinct miRNA profiles within the CSF and plasma. Additionally, preliminary work by our group has shown that ex vivo exposure of monocytes from PWH to 9- tetrahydrocannabinol (THC) potently suppresses expression of pivotal inflammasome associated genes. To confirm these observations and further elucidate the impact of cannabis on NLRP3 inflammasome activation, this project will first determine the impact of CB use on systemic inflammation, NLRP3 inflammasome activation, and immune cell function in PWH on ART via immunophenotyping. We will then examine the impact of cannabis use on the “gut-brain immune axis, via assessing markers of intestinal integrity, blood-brain barrier (BBB) permeability and CNS activation. Lastly, we will conduct mechanistic ex vivo single cell transcriptomic experiments aimed at determining the mechanisms by which THC, CBD, and other cannabinoids modulate inflammasome activation in monocytes from our well characterized cohort of cannabis using PWH. This project will elucidate the impact of cannabis use on NLRP3 inflammasome activation in PWH to develop specific therapeutic targets for modulation to reduce inflammation associated HIV comorbidities such as NCI.