Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment

J Infect Dis. 2007 May 15;195(10):1419-25. doi: 10.1086/513872. Epub 2007 Apr 4.


Mitochondrial toxicity is a major adverse effect of the nucleoside reverse-transcriptase inhibitors (NRTIs) used for treatment of human immunodeficiency virus type 1 (HIV-1) infection and can result in life-threatening lactic acidosis. The toxicity is due to inhibition of polymerase gamma (Pol gamma), which is required for replication of mitochondrial DNA (mtDNA). Genetic factors could be involved in this process, given that not all NRTI-treated patients experience the toxicity. In 1 patient with lactic acidosis, a novel homozygous Pol gamma mutation (arginine to cysteine at codon 964 [R964C]) was identified at a site close to polymerase motif B, which is highly conserved among family A polymerases. Recombinant R964C Pol gamma showed only 14% activity, compared with that of wild-type Pol gamma. Culture with stavudine significantly reduced mtDNA levels in patient-derived lymphoblastoid cell lines (LCLs) harboring R964C Pol gamma, compared with those in LCLs harboring wild-type Pol gamma. The novel Pol gamma mutation could be associated with the severe lactic acidosis induced by long-term NRTI use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Anti-HIV Agents / toxicity*
  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / genetics*
  • Exons
  • Female
  • Genetic Carrier Screening
  • Homozygote
  • Humans
  • Lactates / blood
  • Male
  • Mitochondria / drug effects
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Models, Molecular
  • Pedigree
  • Protein Conformation
  • Protein Subunits
  • Reference Values


  • Anti-HIV Agents
  • DNA, Mitochondrial
  • Lactates
  • Protein Subunits
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase