Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus

Abstract

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.

Figure 1.

Mitochondrial DNA (mtDNA) content in frontal cortex samples. A, The mtDNA content decreased with age. B, After correction for age, mtDNA content was lower in human immunodeficiency virus (HIV)–positive cases than controls. Among HIV-positive cases, mtDNA content did not differ according to antiretroviral therapy treatment status at last visit (C) or cognitive function (D). Abbreviations: ART, antiretroviral therapy; GDS, global deficit score; HIV, human immunodeficiency virus; mtDNA, mitochondrial DNA.

Figure 2.

Proportional levels of the mitochondrial DNA common deletion (CD) in frontal cortex samples. A, CD levels increased with age. B, After correction for age, CD levels were higher in human immunodeficiency virus (HIV)–positive cases than controls. Among HIV-positive cases, CD levels did not differ according to antiretroviral therapy treatment status at last visit (C) or cognitive function (D). Abbreviations: ART, antiretroviral therapy; CD, common deletion; GDS, global deficit score; HIV, human immunodeficiency virus; mtDNA, mitochondrial DNA.

Figure 3.

Deep sequencing of heteroplasmic mitochondrial DNA (mtDNA) point mutations (Illumina) in frontal cortex, showing number and type of mutations detected per sample. A, Coding region mutations were more frequent in human immunodeficiency virus (HIV)–positive cases compared with controls (horizontal line shows median, bar shows maximum). B, Number of mutations increased with age and HIV status. C, Mutational burden weighted for variant heteroplasmy levels was higher in HIV-positive cases than controls after adjusting for age. Low CD4/CD8 ratio (D) and cognitive impairment (E) were associated with increased number of mtDNA mutations. Abbreviations: GDS, global deficit score; HIV, human immunodeficiency virus; non-syn, nonsynonymous; rRNA, ribosomal RNA; syn, synonymous; tRNA, transfer RNA.