Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus

Clin Infect Dis. 2021 Jul 15;73(2):e466-e473. doi: 10.1093/cid/ciaa984.


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.

Keywords: HIV; HIV-associated neurocognitive disorders; aging; antiretroviral therapy; mitochondrial DNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Brain
  • DNA, Mitochondrial / genetics
  • HIV
  • HIV Infections* / complications
  • Humans
  • Mitochondria / genetics


  • DNA, Mitochondrial