PROJECT SUMARY/ABSTRACT
Despite antiretroviral therapy (ART), neurocognitive complications continue to be highly prevalent in people
living with HIV (PLWH). One explanation could be the constant compromise of the blood brain barrier (BBB)
driven by chronic inflammatory responses. The introduction of medicinal marijuana into HIV treatment practice
appear to be beneficial for several virus associated complications (ranging from chronic pain to appetite
stimulation). Yet, the effects and mechanisms of cannabis on HIV associated chronic inflammation, the
endocannabinoid system, immune modulation and neurologic disorders are minimally understood. As indicated
in the RFA, preclinical models can provide a rigorous in-depth analysis of the molecular and cellular
mechanisms at the intersection between phytocannabinoids, HIV and ART. To this end, we propose a
comprehensive evaluation of the two most used cannabinoid compounds (THC, CBD) on BBB function,
immune-endothelial interactions and neuroinflammation. We will utilize state of the art chip microfluidics
models of the neurovascular unit (NVU) and animal models for HIV (w/ w/o ART). Previously, we discovered
that the brain endothelium upregulate CB2 in HIV infected human brain tissue. We have also found that
modulation of CB2 affects indices of HIV pathology (in-vivo) and regulates the BBB. Our preliminary studies
identify the diverse effects that phytocannabinoids can have on the different properties of the BBB. Specifically,
cannabinoids (THC, CBD) alone can enhance the physical barrier, partially reduce endothelial activation and
augment efflux transporter activity. Although some of these effects may appear beneficial, the presence of HIV
and ART changes how the function of the BBB is regulated by cannabinoid substances. For example, the
augmented transporter activity by THC has important considerations for altering ART-CNS penetrability. Thus,
we hypothesize that phytocannabinoids differentially modulates BBB function that are both beneficial
and deleterious in NeuroHIV. In Aim 1, using our latest tissue-engineered microfluidic NVU model, we will
perform analyses of the kinetic changes in BBB permeability, transporter status and immune-endothelial
interaction. Then, in Aim 2, we will compare outcomes between widely used routes of cannabinoid
administration (oral vs. inhaled) in vivo using two relevant models of HIV infection (‘humanized’ mice and a
model of aseptic meningitis/encephalitis). Experiments will evaluate changes in the BBB in the context of ART
and cannabinoid exposure. Finally, we propose to identify novel crosstalk mechanisms that bridge cannabinoid
receptor signaling to signals that control BBB maintenance (Aim 3). It’s clear that cannabinoids exert unknown
cell specific effects that contribute to the tumultuous interpretation of how these compounds impact NeuroHIV.
Using innovative preclinical tools, our studies will contribute significantly towards understanding the
consequences of cannabinoid use on the BBB in the modern era of NeuroHIV.
