Pediatric ART Leads to Increasing Mitochondrial DNA Mutations

For children with HIV-1 infection, mitochondrial DNA (mtDNA) mutations accumulate over time with long-term nucleoside reverse-transcriptase inhibitors (NRTI) exposure, according to results published in the Journal of Antimicrobial Chemotherapy.

These results indicated that mtDNA mutations accumulated during antiretroviral therapy (ART) may play an integral role in the occurrence of mitochondrial dysfunction.

The study included children with HIV-1 infection who started ART >2 years earlier who had an excellent virologic response and who had not had changes made to their regimen (n=24). The researchers collected data on corresponding peripheral blood mononuclear cell counts in 2009 (T1), 2010 (T2), and 2013 (T3). They sequenced the entire mtDNA of each participant using next-generation sequencing to reveal the spectrum of mtDNA variants.

The results indicated that mtDNA mutations occurred in a trend of T1<T2<T3 (P =.086). At T3, the number of whole mtDNA mutations (median 41, range 24-62) were significantly greater compared with T1 (median 34, range 25-46; P =.029).

The researchers found a positive correlation between total mtDNA mutations and treatment time (r =.0352, P =.002).

The results indicated that mtDNA mutations occurred more frequently in the D-loop, cytochrome b (CYTB), and 12S rRNA regions.

The researchers found that the heteroplasmic ratio of T3 was higher compared with T1 in cytochrome b (CYTB) and 12S subunits of rRNA (P =.034 and P =.042, respectively). They found high heteroplasmic population levels at nucleotide locus 263 (A263G, D-loop) and nucleotide locus 8860 (A8860G, ATPase6). A significant difference in heteroplasmy between T1, T2, and T3 occurred at nucleotide locus 14783 (T14783C, CYTB, P =.048, T3>T2>T1).

Study investigators noted that “NRTIs may cause an increased risk of mtDNA mutations and may provide conditions favorable for mtDNA mutations. It is plausible that one of the mechanisms may be via the acceleration of the clonal expansion of pre-existing (age-associated) mtDNA mutations,” and they concluded, “The mtDNA mutations under current first-line pediatric ART regimens should be addressed in the near future.”

Reference

Ouyang Y, Wei F, Qiao L, et al. Mitochondrial DNA mutations accumulated in HIV-1-infected children who have an excellent virological response when exposed to long-term antiretroviral therapy. J Antimicrob Chemother. 2018;73:3114-3121.