Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress

Abstract

Objectives: HIV and antiretroviral (ART) exposure in utero may have deleterious effects on the infant, but uncertainty still exists. The objective of this study was to evaluate aspects of mitochondrial DNA (mtDNA) content, mitochondrial function and oxidative stress simultaneously in placenta, umbilical cord blood and infant blood in HIV/ART-exposed infants compared with uninfected controls.

Methods: HIV-1-infected pregnant women and HIV-1-uninfected healthy pregnant controls were enrolled in the study prospectively. Placenta and umbilical cord blood were obtained at delivery and infant blood was obtained within 48 h of delivery. mtDNA content was determined for each specimen. Nuclear [subunit IV of cytochrome c-oxidase (COX IV)]- and mitochondrial (COX II)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase were quantified in cord and infant blood. Placental mitochondria malondialdehyde (MDA) concentrations were measured as a marker of oxidative stress.

Results: Twenty HIV-positive/HIV-exposed and 26 control mother-infant pairs were enrolled in the study. All HIV-infected women and their infants received ART. Placental MDA concentration and mtDNA content in placenta and cord blood were similar between groups. The cord blood COX II:IV ratio was lower in the HIV-positive group than in the controls, whereas the infant peripheral blood mtDNA content was higher in the HIV-exposed infants, but the infant peripheral blood COX II:IV ratio was similar. No infant had clinical evidence of mitochondrial disease or acquired HIV infection. In multivariable regression analyses, the significant findings in cord and infant blood were both most associated with HIV/ART exposure.

Conclusions: HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART-associated mitochondrial toxicity.

Fig. 1

Box and whisker plots depicting the distribution of values for (a) umbilical cord blood cytochrome c-oxidase subunit (COX) II:IV ratio and (b) infant peripheral blood mitochondrial DNA (mtDNA) content in the HIV-positive/HIV-exposed subjects and the HIVnegative/ HIV-unexposed controls. Centre lines for each plot represent the median, and the top and bottom lines represent the 25th and 75th percentiles, respectively. Please note that the COX II:IV ratio is depicted on a logarithmic scale to allow accurate depiction of the distribution of the values for both groups. PBMC, peripheral blood mononuclear cell.