Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis
Year: 2022
Type: article
Abstract: 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.
Source: Biomedicines
Institution: Albert Einstein College of Medicine
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,303
Funders: Leukemia Research Foundation, Instituto Nacional de Cancerología, National Institutes of Health, National Institute on Aging, National Institute on Drug Abuse, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Services Industriels de Genève
Awards: G1159308821, G1275800971, G1372999414, G1557182087, G1583220925, Orbitrap Exploris 480 Basic System, G1857499104, G1924491507, G2051864048, G2192564234, G2211944594, G2425984972, G2463638256, G252335265, G2576755164, G2692686562, G2745100336, G2810722554, G3041630884, G3099666453, G3117890672, G3228787220, G323459592, G3433515134, G3622433565, Advanced Confocal Microscope in a multi-user facility, G3795979262, G3798720003, G3849861977, G3901712998, G3914350421, G4022881664, G422565461, G423460813, G4611183783, G4733156781, G4941441753, G5006641767, G503200962, G513155522, G5490547647, G6314222485, G6412745977, G6451293773, G651132157, G6834020828, G6933228818, G7054978880, G7219920267, G7770470996, G8020057958, G8772567148, Cancer Center Support Grant
OpenAlex ID: W4282003010