title: Antiretroviral nucleoside analogues suppress antibody synthesis in human B-lymphocytes.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Setzer
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Walker
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000907:Antibodies, Bacterial; D004272:DNA, Mitochondrial; D018089:Superantigens; D015847:Interleukin-4