Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Neurocognitive impairment (NCI) is prevalent in people living with human immunodeficiency virus (PLWH) despite effective antiretroviral therapy (ART).
• Mitochondrial dysfunction is implicated in aging and neurodegenerative diseases.
• The role of HIV or ART in causing brain mitochondrial abnormalities contributing to NCI is not fully understood.

Purpose of the Study:

• To investigate the impact of HIV and ART on mitochondrial DNA (mtDNA) integrity in the brain.
• To determine if mitochondrial abnormalities correlate with neurocognitive impairment in PLWH.

Main Methods:

• Analysis of postmortem brain samples from 52 PLWH and 40 HIV-negative controls.
• Quantification of cellular mtDNA content, large-scale mtDNA deletions, and heteroplasmic mtDNA point mutations.
• Correlation of mtDNA changes with neurocognitive data and ART exposure.

Main Results:

• Aging was associated with decreased mtDNA content, increased mtDNA deletions, and increased mtDNA point mutations.
• These age-associated mtDNA changes were significantly exacerbated in PLWH compared to controls.
• ART exposure was not linked to mtDNA alterations; however, mtDNA point mutations correlated with lower CD4/CD8 ratio and NCI.

Conclusions:

• HIV infection, rather than ART, drives accelerated age-associated mtDNA damage in the brain.
• This HIV-induced mitochondrial dysfunction may be a key factor contributing to NCI in PLWH.
• Mitochondrial dysfunction could mediate adverse aging phenotypes in individuals living with HIV.