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.

Grant Number: 5R03DA060076-02
NIH Institute/Center: NIH
Principal Investigator: Subhash Chand