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

Hikaru Yamanaka, Hiroyuki Gatanaga, Pope Kosalaraksa, Saori Matsuoka-Aizawa, Takao Takahashi, Satoshi Kimura, Shinichi Oka

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Abstract

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 γ (Pol γ), 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 γ 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 γ showed only 14% activity, compared with that of wild-type Pol γ. Culture with stavudine significantly reduced mtDNA levels in patient-derived lymphoblastoid cell lines (LCLs) harboring R964C Pol γ, compared with those in LCLs harboring wild-type Pol γ. The novel Pol γ mutation could be associated with the severe lactic acidosis induced by long-term NRTI use.

Original languageEnglish
Pages (from-to)1419-1425
Number of pages7
JournalJournal of Infectious Diseases
Volume195
Issue number10
DOIs
Publication statusPublished - 2007 May 15

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Lactic Acidosis
Reverse Transcriptase Inhibitors
DNA-Directed DNA Polymerase
Nucleosides
HIV
Mitochondrial DNA
Mutation
Stavudine
Cell Line
Virus Diseases
Codon
Cysteine
Arginine
HIV-1
Therapeutics

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Novel mutation of human DNA polymerase γ associated with mitochondrial toxicity induced by anti-HIV treatment. / Yamanaka, Hikaru; Gatanaga, Hiroyuki; Kosalaraksa, Pope; Matsuoka-Aizawa, Saori; Takahashi, Takao; Kimura, Satoshi; Oka, Shinichi.

In: Journal of Infectious Diseases, Vol. 195, No. 10, 15.05.2007, p. 1419-1425.

Research output: Contribution to journalArticle

Yamanaka, H, Gatanaga, H, Kosalaraksa, P, Matsuoka-Aizawa, S, Takahashi, T, Kimura, S & Oka, S 2007, 'Novel mutation of human DNA polymerase γ associated with mitochondrial toxicity induced by anti-HIV treatment', Journal of Infectious Diseases, vol. 195, no. 10, pp. 1419-1425. https://doi.org/10.1086/513872
Yamanaka, Hikaru ; Gatanaga, Hiroyuki ; Kosalaraksa, Pope ; Matsuoka-Aizawa, Saori ; Takahashi, Takao ; Kimura, Satoshi ; Oka, Shinichi. / Novel mutation of human DNA polymerase γ associated with mitochondrial toxicity induced by anti-HIV treatment. In: Journal of Infectious Diseases. 2007 ; Vol. 195, No. 10. pp. 1419-1425.
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