HIV Increases the Inhibitory Impact of Morphine and Antiretrovirals on Autophagy in Primary Human Macrophages: Contributions to Neuropathogenesis.

Ana Maria Cuervo,John M Barbaro,Joan W Berman

doi:10.3390/cells10092183

Ana Maria Cuervo, John M Barbaro + Show 1 more

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https://doi.org/10.3390/cells10092183

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Abstract

HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15–40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.

Highlights

38 million people worldwide are living with HIV [1]
We first characterized the impact of morphine (100 nM) and Antiretroviral therapy (ART) (15 μM emtricitabine, 15 μM tenofovir, and 1 μM raltegravir) on autophagy in uninfected primary human monocyte-derived macrophages (MDM) by Western blotting
Cells treated with MOR+ART displayed an increase in LC3II of 1.38-fold, which was mostly driven by ART, as ART treatment alone increased LC3II by 1.22-fold (Figure 1B, p = 0.08 one-sample t-test)

Summary

Introduction

38 million people worldwide are living with HIV [1]. Antiretroviral therapy (ART) has dramatically improved both the length and quality of life for people with HIV (PWH), yet comorbidities persist that can increase morbidity and mortality [2]. Our laboratory and others have shown that HIV enters the CNS by a subpopulation of mature monocytes expressing CD14, the LPS coreceptor, and CD16, the FcγIII receptor [5]. Cell functions of macrophages are dysregulated in the context of HIV to perpetuate neuroinflammation that contributes to neuronal damage and loss and, HAND development. These include aberrant phagocytosis that diminishes clearance of neurotoxic debris, increased reactive oxygen and nitrogen species (ROS/RNS) production that activates other cells, and increased inflammatory cytokines that injure neurons directly and recruit more uninfected and infected immune cells into the CNS [10,11,12]

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