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Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus

Lookup NU author(s): Carla Roca Bayerri, Dr Fiona Robertson, Dr Angela Pyle, Professor Gavin Hudson, Dr Brendan PayneORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.BACKGROUND: Neurocognitive impairment (NCI) remains common in people living with human immunodeficiency virus (PLWH), despite suppressive antiretroviral therapy (ART), but the reasons remain incompletely understood. Mitochondrial dysfunction is a hallmark of aging and of neurodegenerative diseases. We hypothesized that human immunodeficiency virus (HIV) or ART may lead to mitochondrial abnormalities in the brain, thus contributing to NCI. METHODS: We studied postmortem frozen brain samples from 52 PLWH and 40 HIV-negative controls. Cellular mitochondrial DNA (mtDNA) content and levels of large-scale mtDNA deletions were measured by real-time polymerase chain reaction. Heteroplasmic mtDNA point mutations were quantified by deep sequencing (Illumina). Neurocognitive data were taken within 48 months antemortem. RESULTS: We observed a decrease in mtDNA content, an increase in the mtDNA "common deletion," and an increase in mtDNA point mutations with age (all P < .05). Each of these changes was exacerbated in HIV-positive cases compared with HIV-negative controls (all P < .05). ART exposures, including nucleoside analogue reverse transcriptase inhibitors, were not associated with changes in mtDNA. The number of mtDNA point mutations was associated with low CD4/CD8 ratio (P = .04) and with NCI (global T-score, P = .007). CONCLUSIONS: In people with predominantly advanced HIV infection, there is exacerbation of age-associated mtDNA damage. This change is driven by HIV per se rather than by ART toxicity and may contribute to NCI. These data suggest that mitochondrial dysfunction may be a mediator of adverse aging phenotypes in PLWH.


Publication metadata

Author(s): Roca-Bayerri C, Robertson F, Pyle A, Hudson G, Payne BAI

Publication type: Article

Publication status: Published

Journal: Clinical Infectious Diseases

Year: 2021

Volume: 73

Issue: 2

Pages: e466-e473

Print publication date: 15/07/2021

Online publication date: 28/07/2021

Acceptance date: 14/07/2021

Date deposited: 25/08/2021

ISSN (print): 1058-4838

ISSN (electronic): 1537-6591

Publisher: Oxford University Press

URL: https://doi.org/10.1093/cid/ciaa984

DOI: 10.1093/cid/ciaa984

PubMed id: 32722761


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Funding

Funder referenceFunder name
B. A. I. P. reports an infrastructure grant from the Wellcome Centre for Mitochondrial Research, outside the submitted work.
Data Coordinating Center, grant number U24MH100925).
California NeuroAIDS Tissue network, grant number U24MH100928;
National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke (Manhattan HIV Brain Bank, grant number U24MH100931
National Neurological AIDS Bank, grant number U24MH100929;
Texas NeuroAIDS Research Center, grant number U24MH100930;
Wellcome (grant numbers 109975/Z/15/Z, 203105/Z/16/Z)

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