Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers

被引:143
作者
Poirier, MC
Divi, RL
Al-Harthi, L
Olivero, OA
Nguyen, V
Walker, B
Landay, AL
Walker, VE
Charurat, M
Blattner, WA
机构
[1] NCI, Carcinogen DNA Interact Sect, NIH, Bethesda, MD 20892 USA
[2] Rush Med Coll, Dept Microbiol Immunol, Chicago, IL 60612 USA
[3] Lovelace Resp Res Inst, Inhalat Toxciol Lab, Albuquerque, NM USA
[4] Inst Human Virol, Baltimore, MD USA
关键词
lymphocytes; Women and Infants Transmission Study; nucleoside reverse transcriptase inhibitor; telomere; mitochondrial DNA;
D O I
10.1097/00126334-200306010-00010
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Although children born to HIV-infected (HIV+) women receiving antiretroviral therapy during pregnancy show virtually no adverse clinical effects at birth, the antiretroviral nucleoside analog drugs are known to damage nuclear and mitochondrial DNA. In this study, biomarkers of mitochondrial toxicity and genotoxicity have been examined in a well-characterized sample set consisting of infants born to HIV-uninfected (HIV-) mothers (n = 30), and HIV- infants (n = 20) born to HIV-infected (HIV+) mothers who received either no antiretroviral therapy (n = 10) or zidovudine (3'-azido-3'-deoxythymidine [AZT]) during pregnancy (n = 10). DNA from cord blood leukocytes and peripheral blood leukocytes taken at 1 and 2 years of age was examined for loss of mitochondrial DNA (mtDNA) and telomere integrity. Telomere length, a measure of nuclear DNA damage, was the same in all infants at birth and at age 1 year. The quantity of mtDNA was assessed relative to nuclear DNA using a polymerase chain reaction-based chemiluminescence detection (PCR-CID) method that determined mitochondrial D Loop gene copies relative to nuclear 18S RNA gene copies by comparison with a standard curve. MtDNA quantity was expressed as a ratio of gene copy numbers. In infants of uninfected mothers (AZT-/HIV-) at the three time points, the ratios were 442 to 515, whereas in infants of untreated AZT-/HIV+ mothers the ratios were 261 to 297, and in infants of AZT-treated (AZT(+)/HIV+) mothers the ratios were 146 to 203. At all three time points, differences between the AZT-/HIV group and the two HIV+ groups were statistically significant (p <.05), and differences between the AZT-/HIV+ and AZT(+)/HIV+ groups were also statistically significant (p <.05), demonstrating that AZT exposure causes a persistent depletion of mtDNA. The study shows that children of HIV+ mothers are at risk for mitochondrial damage that is further increased in infants of mothers receiving AZT during pregnancy.
引用
收藏
页码:175 / 183
页数:9
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