Grant: Doctoral: Vanier Canada Graduate Scholarships

There are ~3 million HIV pregnancies each year. To prevent mother-to-child transmission, HIV-infected pregnant women receive antiretroviral therapy (ART) that consists of at least three drugs. It reduces the risk of transmission from ~25% to <1%. AZT, a heavily used HIV drug in pregnancy, can cross the placenta and affect mitochondria, the energy producing organelles within cells. Mitochondria have their own DNA (mtDNA); the replication of which is inhibited by AZT. This can cause mtDNA depletion, deletions and mutations. MtDNA mutations have been associated with aging and age-associated diseases such as Alzheimer's and cancer. This begs the question, "Do HIV-uninfected children exposed to AZT in utero (in the womb) have more mtDNA damage and a higher risk of developing age-associated diseases earlier than the general population?" There are no studies to date on the long-term molecular effects of ART exposure in utero, specifically with respect to mtDNA mutations in children. The objective of this project is to determine whether HIV-uninfected but ART-exposed infants born to HIV-infected mothers show increased blood cell mtDNA mutations compared to infants who were never exposed. Also, the effects of various ART combinations (several drugs and combinations are used) on mtDNA mutations in different cell culture systems will be studied. This could allow the study of less toxic drugs that are not used in pregnancy due to the lack of clinical trial data. The results from my project will increase our knowledge and understanding of HIV ART mitochondrial toxicity and mtDNA damage in pregnancy. It may also suggest that in utero exposure to the most commonly prescribed AZT is associated with long-term toxicity and that other drugs on the market may be more appropriate for use during pregnancy. Ultimately, this research aims to improve treatment guidelines and inform future clinical trials to maximize prevention of HIV transmission while minimizing risks to the infants.