Some antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) impair mitochondrial polymerase-γ and T-cell proliferation, possibly by pyrimidine depletion. We aimed to analyse NRTI effects on the content of mitochondrial DNA (mtDNA) and B-cells, and on their proliferation and antibody synthesis.
Methods
Peripheral blood B-lymphocytes from six healthy individuals were stimulated in vitro with interleukin-4 and Staphylococcus aureus superantigen in the presence or absence of NRTI in concentrations equivalent to, or fivefold exceeding, human peak plasma levels. We also tested the effects of uridine, a pyrimidine precursor, which has antagonized NRTI toxicities in other models.
Results
During 9 days of culture, B-lymphocyte proliferation and vitality were not affected by NRTI. Didanosine and stavudine, but not zidovudine, dose-dependently induced mtDNA depletion. All three NRTI significantly and dose-dependently impaired the synthesis of all immunoglobulin classes. The lymphocytotoxic effects of the thymidine analogues zidovudine and stavudine on B-lymphocytes were antagonized by the addition of uridine.
Conclusions
Didanosine, stavudine and zidovudine induce mitochondrial toxicity in human B-lymphocytes and impair the immunoglobulin synthesis in vitro, warranting further studies on their in vivo effects.
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