Extensive investigations of mitochondrial DNA genome in treated HIV-infected subjects - Beyond mitochondrial DNA depletion

Background: Therapy with nucleoside reverse transcriptase inhibitor (NRTI) agents has been associated with lipoatrophy and lactic acidosis, presumably through inhibition of DNA polymerase-gamma and resultant mitochondrial DNA (mtDNA) depletion. In past investigations, studies have looked at mtDNA depletion and a few specific mutations but not at the entire mtDNA genome to correlate with clinical toxicity. Methods: This is the largest prospective longitudinal study to date that has performed a complete analysis of the entire mtDNA genome in addition to mtDNA depletion. The study population included 54 HIV-infected NRTI-treated patients with or without clinical mitochondrial toxicities, 33 HIV-infected NRTI-naive patients, and 48 age-matched healthy volunteers. Data on demographics, treatment, and clinical characteristics were collected and blood was drawn for mtDNA analysis, serum fasting lipids, and lactate. Results: No depletion was found in blood mtDNA levels of subjects with clinical mitochondrial toxicities; duration of NRTI therapy was the only predictor of mtDNA levels. After complete analysis of the mtDNA genome, only 2 subjects shoved development of mutations during the study period, after 14 and 52 months of antiretroviral therapy. Conclusion: Blood mtDNA content is not associated with the use of specific NRTIs, nor does it predict clinical symptoms such as lipoatrophy. The only factor associated with mtDNA depletion was duration of NRTI use. Complete mutational analysis of the mitochondrial genome revealed mtDNA mutations in 2 patients. More extensive studies of mtDNA mutation at the single molecule level are required to correlate mitochondrial dysfunction with NRTI-caused molecular defects in mtDNA.