Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations

There is emerging evidence that people with successfully treated HIV infection age prematurely leading to progressive multi-organ disease (1), but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs (NRTIs) progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring that seen much later in life due to normal aging (2,3). Ultra-deep re-sequencing-by-synthesis, combined with single cell analyses, suggests that the increase in somatic mutation is not due to increased mutagenesis, but might be due to accelerated mtDNA turnover. This leads to the clonal expansion of pre-existing age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process, and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade.