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 gamma, 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.

FIGURE 1

Levels of mtDNA in the PBMCs of 411 healthy children who were born to HIV-uninfected women. Shown is a scatterplot of PBMC mtDNA levels on a logarithmic scale in healthy children, according to age. Each circle represents a single individual; the solid line denotes the mean.

FIGURE 2

Box-and-whisker plots on a logarithmic scale of PBMC mtDNA levels in healthy children and in HIV-exposed, uninfected children, according to exposure category and age. Upper and lower box borders represent the 75th and 25th percentiles, solid lines represent the median, dashed lines represent the mean, and error bars represent the 10th and 90th percentiles. ^a P <.001 versus controls; ^b P <.02 versus no ARV exposure group within same age category; ^c P < .001 versus no ARV exposure group within same age category. 3TC indicates lamivudine.