Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy

TLDR

Long‑term zidovudine therapy in HIV patients can cause a destructive mitochondrial myopathy characterized by ragged‑red fibres and abnormal mitochondria. The myopathy results from zidovudine‑induced inhibition of mitochondrial DNA replication by DNA polymerase γ, rather than a secondary effect of HIV infection. In nine zidovudine‑treated patients, muscle mtDNA was reduced by up to 78 % compared with controls, whereas HIV‑positive patients not exposed to zidovudine had normal mtDNA, and one patient showed reversal of depletion after zidovudine discontinuation.

Abstract

Long-term zidovudine therapy in patients with human immunodeficiency virus (HIV) infection can cause a destructive mitochondrial myopathy with histological features of ragged-red fibres (RRF) and proliferation of abnormal mitochondria. In 9 zidovudine-treated patients with this myopathy we found severely reduced amounts (up to 78% reduction vs normal adult controls) of mitochondrial DNA (mtDNA) in muscle biopsy specimens by means of Southern blotting. In 2 HIV-positive patients who had not received zidovudine, muscle mtDNA content did not differ from that in the 4 controls. Depletion of mtD NA seems to be reversible, since 1 patient showed a substantial reduction in RRF and a concomitant pronounced increase in muscle mtDNA content after zidovudine therapy was discontinued. Depletion of muscle mtDNA is probably due to zidovudine-induced inhibition of mtDNA replication by DNA polymerase gamma and is not a secondary effect of HIV infection.