Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription.

Catherine Demarino,Cohava Gelber,Dianne Langford,Fatah Kashanchi,Bianca Cotto,Maria Cowen,Cecilia T Costiniuk,Pooja Khatkar,Heather Branscome,Sarah Al Sharif,Emmanuel T Agbottah,Lance A Liotta,Mohammad-Ali Jenabian,Weidong Zhou,Yuriy Kim

doi:10.3390/cells11040723

Abstract

Of the 37.9 million individuals infected with human immunodeficiency virus type 1 (HIV-1), approximately 50% exhibit HIV-associated neurocognitive disorders (HAND). We and others previously showed that HIV-1 viral RNAs, such as trans-activating response (TAR) RNA, are incorporated into extracellular vesicles (EVs) and elicit an inflammatory response in recipient naïve cells. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the primary cannabinoids present in cannabis, are effective in reducing inflammation. Studies show that cannabis use in people living with HIV-1 is associated with lower viral load, lower circulating CD16+ monocytes and high CD4+ T-cell counts, suggesting a potentially therapeutic application. Here, HIV-1 infected U1 monocytes and primary macrophages were used to assess the effects of CBD. Post-CBD treatment, EV concentrations were analyzed using nanoparticle tracking analysis. Changes in intracellular and EV-associated viral RNA were quantified using RT-qPCR, and changes in viral proteins, EV markers, and autophagy proteins were assessed by Western blot. Our data suggest that CBD significantly reduces the number of EVs released from infected cells and that this may be mediated by reducing viral transcription and autophagy activation. Therefore, CBD may exert a protective effect by alleviating the pathogenic effects of EVs in HIV-1 and CNS-related infections.

Highlights

HIV associated neurocognitive disorder (HAND) is a spectrum of disorders associated with human immunodeficiency virus type 1 (HIV-1) infection
We and others previously showed that extracellular vesicles (EVs) released from virally infected cells contain viral products that contribute to viral pathogenesis, chronic inflammation in those with long-term infections such as HIV-1 [5,10,30]
We showed that EVs released from infected cells contain harmful viral proteins and RNAs despite treatment with HIV-1 specific antiretrovirals as well as general antivirals such as interferon-α [5], suggesting a need for improved therapies which target EV-mediated mechanisms in HIV-1 infection

Summary

Introduction

HIV associated neurocognitive disorder (HAND) is a spectrum of disorders associated with human immunodeficiency virus type 1 (HIV-1) infection. Since the widespread use of combined antiretroviral therapy (cART) in 1996, there was a marked reduction in the number of people with HIV (PWH) diagnosed with HAND, the prevalence is still currently estimated to be 20–50% of HIV-1 infected individuals [2]. While the relative percentage of those with severe cognitive impairment has decreased, the percentage of PWH with ANI has increased. This trend is promising, the propensity to develop HAD is increased in individuals with ANI compared to those with normal neurocognitive function [3]. The inability of cART to completely suppress neurocognitive dysfunction illustrates a need for adjunct therapies that target the underlying neuropathology

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