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Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis

HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage i...

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Autores principales: Barbaro, John M., Sidoli, Simone, Cuervo, Ana Maria, Berman, Joan W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220012/
https://www.ncbi.nlm.nih.gov/pubmed/35740279
http://dx.doi.org/10.3390/biomedicines10061257
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author Barbaro, John M.
Sidoli, Simone
Cuervo, Ana Maria
Berman, Joan W.
author_facet Barbaro, John M.
Sidoli, Simone
Cuervo, Ana Maria
Berman, Joan W.
author_sort Barbaro, John M.
collection PubMed
description HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth.
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spelling pubmed-92200122022-06-24 Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis Barbaro, John M. Sidoli, Simone Cuervo, Ana Maria Berman, Joan W. Biomedicines Article HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth. MDPI 2022-05-27 /pmc/articles/PMC9220012/ /pubmed/35740279 http://dx.doi.org/10.3390/biomedicines10061257 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barbaro, John M.
Sidoli, Simone
Cuervo, Ana Maria
Berman, Joan W.
Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title_full Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title_fullStr Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title_full_unstemmed Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title_short Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
title_sort methamphetamine dysregulates macrophage functions and autophagy to mediate hiv neuropathogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220012/
https://www.ncbi.nlm.nih.gov/pubmed/35740279
http://dx.doi.org/10.3390/biomedicines10061257
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