Tuesday, April 1, 2025
4/1/2025
Impact of cannabidiol on HIV infection and methamphetamine abuse associated neuroinflammation - Abstract: Although there is an 8% decrease in HIV infection in the U.S., the prevalence of people with HIV (PWH) has increased due to effective combinational antiretroviral therapy (cART). PWH are prone to substance abuse such as methamphetamine (METH), opioids, cannabis, and alcohol. Moreover, HIV and substance abuse constitutes a health syndemic and contribute to a significant economic burden to the U.S. PWH and, with METH abuse, have activated and inflamed immune systems, increasing the risk of neurocognitive disorders (NCD). HIV and METH increase neuroinflammation, whereas cannabidiol (CBD), a component of cannabis, is known to attenuate inflammation; however, their collective impact is yet to be elucidated. Thus, there is a critical need to delineate the mitigating effect of CBD on neuroinflammation in HIV infection and METH abuse. Our long-term goal is to establish effective intervention strategies to enhance PWH's span and quality of life. Our overall objective for this proposal is to understand the impact of CBD on HIV infection and METH abuse- associated neuroinflammation. In recent times, extracellular vesicles (EVs) have gained considerable attention as novel actors in intercellular communication, inflammation, and disease progression. On the other hand, depending on the cell of origin, EVs can have precisely the opposite effect, i.e., alleviate inflammation. Several preclinical studies have indicated CBD alleviates inflammation by inhibiting NLRP3 inflammasome activation and cytokine production. However, the underpinning mechanism of CBD's effects on neuroinflammation in the context of HIV infection and METH abuse has not been explored. Based on the previous findings, we hypothesize that CBD attenuates HIV and METH abuse-associated neuroinflammation by modulating NLRP3 inflammasome activation and altering the EV cargo. We will test this hypothesis under the following two aims; In Aim 1, we will evaluate the effect of CBD in modulating NLRP3 inflammasome activation and EV cargo in vitro. We will use human monocyte-derived microglia (MDMi) in our study. RNA and protein isolated from different experimental groups will be used to analyze gene expression, whereas EVs isolated from conditioned media will be subjected to cytokines analysis. In Aim 2, we will investigate the effect of CBD on neuroinflammation and EV cargo in HIV infection and METH abuse using a Hu-mice model. Preclinical hu-mice models with METH administration and HIV infection that exhibit pathophysiological complexities of the human brain will accurately mimic neuroinflammation in clinical settings. Thus, delineating the impact of CBD on the modulation of neuroinflammation in the context of HIV infection and METH abuse will identify genes involved in neuroinflammation and NLRP3 inflammasome activation during HIV infection and METH abuse and the impact of CBD administration.
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