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

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.