Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns.

Audrey Monnin,Thorkild Tylleskar,Mandisa Singata-Madliki,Valérie Desquiret-Dumas,Pascal Reynier,Jean-Pierre Molès,Chipepo Kankasa,Nicolas Nagot,Vincent Procaccio,Céline Bris,Nicolas Méda,David Goudenège,Philippe Van De Perre

doi:10.3390/jcm10112399

Abstract

Worldwide, one million HIV-exposed uninfected (HEU) children are born yearly, and chronic health impairments have been reported in these children. Mitochondrial DNA (mtDNA) instability and altered mtDNA content have been evidenced in these children, but an exhaustive characterization of altered mitochondrial genomes has never been reported. We applied deep mtDNA sequencing coupled to the deletion identification algorithm eKLIPse to the blood of HEU neonates (n = 32), which was compared with healthy controls (n = 15). Dried blood spots (DBS) from African HEU children were collected seven days after birth between November 2009 and May 2012. DBS from French healthy controls were collected at birth (or <3 days of life) in 2012 and in 2019. In contrast to the absence of mtDNA instability observed at the nucleotide level, we identified significant amounts of heteroplasmic mtDNA deletions in 75% of HEU children and in none of controls. The heteroplasmy rate of the 62 mtDNA deletions identified varied from 0.01% to up to 50%, the highest rates being broadly compatible with bioenergetic defect and clinical expression. mtDNA integrity is commonly affected in HEU neonates. The nature of the deletions suggests a mechanism related to aging or tumor-associated mtDNA instability. This child population may be at risk of additional mtDNA genetic alterations considering that they will be exposed to other mitotoxic drugs including antiretroviral or anti-tuberculosis treatment.

Highlights

Each year, almost one million children are born to HIV-infected mothers but are uninfected themselves (HIV-Exposed Uninfected (HEU) children) [1]
We investigated the association between having mitochondrial DNA (mtDNA) deletions at day seven and the following explanatory variables, using Poisson regressions with robust error variance: sex, gestational age, weight of the child at day seven, study site, age of the mother, maternal viral load at D7, duration of ZDV prophylaxis taken during pregnancy and alcohol consumption during pregnancy
The sex ratio was close to 1:1, but it was 2:1 in the control group. Their growth indicators were in the normal range according to WHO standards and did not differ from the values of the other children enrolled in the trial when matched by country

Summary

Introduction

Almost one million children are born to HIV-infected mothers but are uninfected themselves (HIV-Exposed Uninfected (HEU) children) [1]. The factors responsible for these health impairments are not fully understood, but it has been suggested that they result from antiretroviral (ARV) and/or HIV exposure(s), both during intra uterine life and breastfeeding. ARVs, and nucleoside reverse transcriptase inhibitors (NRTI), are well known for their mitochondrial genotoxicity due to the inhibition of the replication of the mitochondrial DNA (mtDNA) [17,18]. In the HIV context, this ROS production is enhanced by NRTI [21], chronic inflammation, and HIV-free proteins such as Gp120, Tat, Nef, and Vpr [22]

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Results

Conclusion