Mitoquinone mesylate attenuates brain inflammation in humanized mouse model of chronic HIV infection
Year: 2022
Type: article
Abstract: Despite effective antiretroviral treatment (ART), people with HIV (PWH) are predisposed to age-related conditions, such as HIV-associated neurocognitive disorders (HAND) that may impact more than 25% of PWH [1].Thus, ART alone is inadequate treatment for HAND and there is an unmet need for novel therapies for HAND.Persistent viral reservoirs, despite ART, impact innate immune cells and microglia leading to oxidative stress (OS), inflammation, immune activation and ultimately neurotoxicity [1] that contribute to pathogenesis of HAND [2].The brain is enriched in mitochondria that are responsible for most of the cellular reactive oxygen species (mito-ROS) [2].HIV-1 promotes aberrant production of mito-ROS that induce mitochondrial and cellular damage and inflammatory signaling pathways [3,4] that drive pathology of neurodegenerative disorders [2,5].The mitochondrial antioxidant MitoQ (MitoQ Ltd, Auckland, New Zealand) can target the harmful production of mito-ROS and may also attenuate secretion of IL-1β and IL-6 that contribute to neuroinflammation in HAND [3,4].Thus, we hypothesized that MitoQ may be effective in reducing neuroinflammation that leads to HAND.Herein, using a preclinical mouse model of chronic HIV, we demonstrate that MitoQ can attenuate proinflammatory cytokines and chemokines in the brain of HIV-1-infected humanized mice on ART.NOD scid gamma (NSG) Bone Marrow and Liver Thymic (BLT) mice (equal number of males and females; n = 27) were generated, as described [6] in accordance with federal, state, and local-approved guidelines.NSG BLT mice were infected with dual-tropic HIV-1 89.6 and treated with daily ART [Tenofovir Disoproxil Fumarate (8.75 mg/kg)/Emtricitabine (13 mg/kg)/Raltegravir (17.5 mg/kg)] as previously described [6].Mice were administered for 90 days 500 mmol/l MitoQ via drinking flavored water as previously [7].Control mice did not receive MitoQ.Three groups were used: uninfected (group A: HIV -, n = 5), infected and on ART (group B: HIV + ART + , n = 12), and infected on ART and MitoQ
Source: AIDS
Institution: University of California, Los Angeles
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: California Institute for Regenerative Medicine, amfAR, The Foundation for AIDS Research, National Institutes of Health, Center for AIDS Research, University of Washington, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Center for AIDS Research, University of California Los Angeles
Awards: G1319225034, G1395318438, Humanized mice as a model to study the role of oxidized lipids in HIV-related cardiovascular disease, G2410412072, The role of CD4 in macrophage differentiation and function, G2972195562, In vivo modelling of therapeutic strategies for prevention of HIV-related fibrosis and fatty liver disease in chronic treated HIV-1 infection, G3815526062, Stem Cell Programming With Chimeric Antigen Receptors to Eradicate HIV Infection, Oxidized HDL in the intersection of HIV, immune activation and atherosclerosis, Anti-HIV Gene Therapy: Defend and Attack, Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV, Targeting Type I Interferon Immune Activation to Control HIV Infection in vivo, G6119132002, Selective Tuning of Stem Cell Extracellular Vesicles as a Novel Therapy for Age-related Tendinopathy, Humanized mice as a model to study novel therapies for HIV-Associated Neurocognitive Disorders (HAND) in elderly HIV-1 infected individuals, Elucidating the impact of molecular signatures of immune senescence on aging in chronic treated HIV, UCLA Center for AIDS Research (CFAR), UCLA Maximizing Student Development (MSD) Program
OpenAlex ID: W4292242325