Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-γ inhibition

Clin Pharmacol Ther. 2014 Jul;96(1):110-20. doi: 10.1038/clpt.2014.64. Epub 2014 Mar 17.


We hypothesized that competition between nucleotide reverse-transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase-γ (pol-γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV-infected patients with mitochondrial toxicity, 25 HIV-infected positive controls, and 25 HIV-negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090-12,590), 4,360 (IQR: 3,058-6,838), and 2,968 (IQR: 2,538-4,436) pmol/10(6) cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol-γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)-binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART-induced mitochondrial toxicity independent of pol-γ inhibition.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Anti-HIV Agents / adverse effects*
  • Case-Control Studies
  • DNA Polymerase gamma
  • DNA, Mitochondrial / blood
  • DNA-Directed DNA Polymerase / metabolism
  • Deoxyribonucleotides / blood
  • Female
  • Gene Dosage
  • HIV Infections / drug therapy*
  • HIV Infections / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Nucleic Acid Synthesis Inhibitors*
  • Nucleotide Transport Proteins / metabolism
  • Nucleotides / adverse effects*
  • Reverse Transcriptase Inhibitors / adverse effects*
  • Ribonucleotides / blood


  • ATP-Binding Cassette Transporters
  • Anti-HIV Agents
  • DNA, Mitochondrial
  • Deoxyribonucleotides
  • Nucleic Acid Synthesis Inhibitors
  • Nucleotide Transport Proteins
  • Nucleotides
  • Reverse Transcriptase Inhibitors
  • Ribonucleotides
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase