Antiretroviral Exposure and Lymphocyte mtDNA Content Among Uninfected Infants of HIV-1-Infected Women

Abstract

OBJECTIVE Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase γ, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction. METHODS We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay. RESULTS Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure. CONCLUSIONS Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children.

Mitochondrial dysfunction and human immunodeficiency virus infection

“…The authors found that PBL mtDNA was decreased in HIV-exposed neonates compared to controls, but was higher in ART/ HIV-exposed neonates than HIV-exposed neonates who were not exposed to ART. 71 These data support the notion that HIV itself, and not NRTIs, is the major contributor towards PBL mtDNA depletion. Regarding ART-exposed patients in larger studies, Chiappini et al, 65 Coté et al 68 and De Mendoza et al 66 all found lower levels of PBL mtDNA associated with d4T, DDI and particularly d4T/DDI combination regimens.…”

High Incidence of Invasive Group B Streptococcal Infections in HIV-Exposed Uninfected Infants

“…Several studies showed a depressed hematopoiesis in HEU children, including a decrease in platelets, neutrophils, total lymphocytes, CD4 and CD8 ϩ cell count, 21,22,24,51,52 that might be attributable to mitochondrial dysfunction associated with exposure to nucleoside reverse transcriptase inhibitors (NRTIs). Indeed, NRTIs cross the placenta 53,54 and have an affinity for the mitochondrial ␥ polymerase. It has been shown that mitochondrial DNA of cord blood mononuclear cells is significantly reduced in HEU infants compared with infants who are born to HIVuninfected mothers, 53 and the majority of infants who are exposed to NRTI present transient and asymptomatic hyperlactatemia 55,56 ; however, persistent mitochondrial dysfunction that leads to severe neurologic impairment has been reported in a limited number of HEU infants.…”

Mitochondrial toxicity and caspase activation in HIV pregnant women

“…The few studies on long‐term HAART exposure have focused on foetal and perinatal ARV effects 32, 33, 34, 35, 36, 37, but rarely on maternal‐related problems which may, in turn, affect children.…”