Long-Term Mitochondrial Toxicity in HIV-Uninfected Infants Born to HIV-Infected Mothers

Abstract

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.

Short Communication: Transplacental Nucleoside Analogue Exposure and Mitochondrial Parameters in HIV-Uninfected Children

“…2,3 Recent studies have found significantly higher mtDNA levels in peripheral blood mononuclear cells (PBMCs) of HIV-uninfected infants exposed to NA and to other ARV compared to ARV-unexposed infants at birth and in the first few weeks of life, [4][5][6] possibly to due compensatory mitochondrial activity in response to NA-induced stress. These findings contradict earlier studies, which reported decreased mtDNA in cord blood and PBMCs in ARVexposed infants at birth and at 1 and 2 years of age, [7][8][9] and a recent study that found mtDNA depletion with secondary respiratory chain compromise in placental tissue with ARV exposure. 10 Other findings include significantly lower mitochondrial RNA (mtRNA) levels at birth in NA-exposed vs. unexposed infants 4 and no difference in cytochrome c oxidase protein levels.…”

High False-positive Rate of Human Immunodeficiency Virus Rapid Serum Screening in a Predominantly Hispanic Prenatal Population

“…4 However, AZT is not innocuous. [16][17][18][19] CDC currently recommends that children perinatally exposed to antiretrovirals should have long-term follow-up, including evaluation for late effects of these therapies, such as tumor onset, neurologic and neurodevelopmental deficits. 20,21 With an HIV seroprevalence among Hispanic mothers of 0.05% in our population, the number needed to screen would be more than 16,000 Hispanic gravidas to prevent a single case of perinatal transmission of HIV (based on a 25% baseline risk of vertical transmission and an optimal decrease to 8% with peripartum AZT).…”

Development of 2′-Deoxy-4′-C-Ethynyl-2-Fluoroadenosine (EFdA) which has Supremely High Anti-HIV Activity and Low Toxicity and Prevents the Emergence of Resistant HIV Mutants, and Discovery of Different Substrate Selectivity between Viral and Human Nucleic Acid Polymerases

“…In adipocytes from HAART treated patients, it has also been shown that NRTI administration correlated positively with mitochondrial DNA depletion [41,42] suggesting an etiology for the lipodystrophy imparted by HAART. There are also coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to AZT, alone or in combination with the NRTI 3TC [43,44]. Further it has been demonstrated that placental tissue of HIV-1-infected HAARTexposed pregnancies undergoes mitochondrial DNA depletion with secondary respiratory chain compromise [45] and also that HAART treated pregnant mothers can have children with mitochondrial dysfunction [46].…”