Research Article
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Mutational analysis of the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants receiving AZT-based therapies for prophylaxis of HIV-1
Salina M. Torres,
Dale M. Walker,
Consuelo L. McCash,
Meghan M. Carter,
Jessica Ming,
Edmund M. Cordova,
Rachel M. Pons,
Dennis L. Cook Jr.,
Steven K. Seilkop,
William C. Copeland,
Vernon E. Walker,
Salina M. Torres
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorDale M. Walker
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
BioMosaics, Inc., Burlington, Vermont
Search for more papers by this authorConsuelo L. McCash
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorMeghan M. Carter
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorJessica Ming
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorEdmund M. Cordova
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorRachel M. Pons
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorDennis L. Cook Jr.
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorSteven K. Seilkop
SKS Consulting Services, Siler City, North Carolina
Search for more papers by this authorWilliam C. Copeland
Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina
Search for more papers by this authorCorresponding Author
Vernon E. Walker
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
BioMosaics, Inc., Burlington, Vermont
BioMosaics, Inc., 655 Spear St., Building C, Burlington, VT 05405, USASearch for more papers by this authorSalina M. Torres,
Dale M. Walker,
Consuelo L. McCash,
Meghan M. Carter,
Jessica Ming,
Edmund M. Cordova,
Rachel M. Pons,
Dennis L. Cook Jr.,
Steven K. Seilkop,
William C. Copeland,
Vernon E. Walker,
Salina M. Torres
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorDale M. Walker
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
BioMosaics, Inc., Burlington, Vermont
Search for more papers by this authorConsuelo L. McCash
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorMeghan M. Carter
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorJessica Ming
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorEdmund M. Cordova
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorRachel M. Pons
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorDennis L. Cook Jr.
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Search for more papers by this authorSteven K. Seilkop
SKS Consulting Services, Siler City, North Carolina
Search for more papers by this authorWilliam C. Copeland
Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina
Search for more papers by this authorCorresponding Author
Vernon E. Walker
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
BioMosaics, Inc., Burlington, Vermont
BioMosaics, Inc., 655 Spear St., Building C, Burlington, VT 05405, USASearch for more papers by this authorAbstract
A sensitive vertical denaturing gradient gel electrophoresis (DGGE) method, using 13 unipolar psoralen-clamped PCR primer pairs, was developed for detecting sequence variants in the 22 tRNA genes and flanking regions (together spanning ∼21%) of the human mitochondrial genome. A study was conducted to determine (i) if mitochondrial DNA (mtDNA) polymorphisms and/or mutations were detectable in healthy newborns and (ii) if prepartum 3′-azido-2′,3′-dideoxythymidine (AZT) based HIV-1 prophylaxis was associated with significant increases in mtDNA mutations and changes in the degree of heteroplasmy of sequence variants in uninfected infants born to HIV-1-infected mothers. DGGE analysis of umbilical cord tissue (where vascular endothelium and smooth muscle cells are the major source of mtDNA) showed that mtDNA sequence variants were significantly elevated by threefold in AZT-treated infants compared with unexposed controls (P < 0.001), with 24 changes observed in 19/52 (37%) treated newborns (averaging 0.46 changes/subject) versus only eight changes found in 7/55 (13%) unexposed newborns (averaging 0.15 changes/subject). Six distinct sequence variants occurring in unexposed controls were predominately synonymous and homoplasmic, representing previously reported polymorphisms. Uninfected infants exposed to a combination of AZT and 2′,3′-dideoxy-3′-thiacytidine and “maternal HIV-1” had a significant shift in the spectrum of mutations (P = 0.04) driven by increases in nonsynonymous heteroplasmic sequence variants at polymorphic sites (10 distinct variants) and novel sites (four distinct variants). While the weight of evidence suggests that prepartum AZT-based prophylaxis produces mtDNA mutations, additional research is needed to determine the degree to which fetal responses to maternal HIV-1 infection, in the absence of antiretroviral treatment, contribute to prenatal mtDNA mutagenesis. Environ. Mol. Mutagen., 2009. © 2008 Wiley-Liss, Inc.
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