Novel Mutation of Human DNA Polymerase γ Associated with Mitochondrial Toxicity Induced by Anti‐HIV Treatment

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 g (Pol g), which is required for replication of mitochondrial DNA (mtDNA). Genetic factors could be involved in this process, given that not all NRTItreated patients experience the toxicity. In 1 patient with lactic acidosis, a novel homozygous Pol g 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 g showed only 14% activity, compared with that of wild-type Pol g. Culture with stavudine significantly reduced mtDNA levels in patient-derived lymphoblastoid cell lines (LCLs) harboring R964C Pol g, compared with those in LCLs harboring wild-type Pol g. The novel Pol g mutation could be associated with the severe lactic acidosis induced by long-term NRTI use.

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa

“…[34] Collectively, it can be stipulated that these variants are not common among the black African population. However, whether R964C/ E1143G is a true functional mutation cannot be determined from this study but is evident in previous studies [16,17] conducted in other populations. We cannot exclude the possibility that screening a larger number of patients would have shown some cases of POLG1 mutation associated with NRTI mitochondrial toxicity and SHL.…”

“…The POLG1 mutations associated with NRTI-mitochondrial toxicity to date, R964C and E1143G, [16,17] were not seen in any of the HIV-positive Zulu-speaking patients we screened. A direct relationship between the R964C/E1143G mutation and SHL cannot be determined from this study.…”

“…Cultures in stavudine patient-derived lymphoblastoid cell lines (LCLs) had significantly reduced mtDNA levels compared with the LCLs of wild-type POLG1. [16] Further biochemical analysis of the R964C holoenzyme showed a 33% decrease in dTTP incorporation efficiency and a threefold decreased discrimination for d4TTP compared with the wild-type POLG1. [29] Thus, the POLG1 R964C mutation may be a cause of SHL caused by NRTI-mitochondrial dysfunction.…”

“…[33] The POLG1 R964C mutation has been definitively associated with hyperlactataemia in an HIV-positive Thai female patient undergoing HAART with stavudine. [16] Biochemical analysis demonstrated an 86% reduction in activity of recombinant R964C POLG1 compared with that of wild-type POLG1. Cultures in stavudine patient-derived lymphoblastoid cell lines (LCLs) had significantly reduced mtDNA levels compared with the LCLs of wild-type POLG1.…”

“…[8] In South Africa (SA), SHL/LA incidence appears notably high, [9][10][11][12][13][14][15] especially in KwaZulu-Natal (KZN) Province, which is predominantly inhabited by the SA Zulu-speaking population. [10,12,14] The objective of this study was to detect if known mutations in mtDNA polymerase-γ (POLG1) [16,17] reported to be associated with mitochondrial toxicity are also linked with NRTI-induced SHL/LA in the SA Zulu-speaking population.…”