UBC Theses and Dissertations
Blood mitochondrial DNA mutations in HIV-infected women and their infants exposed to HAART during pregnancy Jitratkosol, Marissa Helene Jeanne
Background/Objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) as part of highly active antiretroviral therapy (HAART) are given to human immunodeficiency virus (HIV)-infected pregnant women to prevent HIV vertical transmission. NRTIs can adversely affect mitochondrial DNA (mtDNA) and may induce mtDNA point mutations. We hypothesised that HAART-exposed/HIV-uninfected infants may show higher blood mtDNA mutation burden than controls born to HIV-uninfected mothers. Methods: Blood was collected from infants exposed in utero to HIV/HAART and controls (0-6d), as well as from a subset of their mothers (last visit before delivery). MtDNA mutation burden was measured by an assay involving cloning and sequencing mtDNA D-loop PCR amplicons. The presence of transversion mutations A → C/T → G (AC/TG) was analysed by Chi-squared and Wilcoxon signed-rank tests. Relationships with amount of DNA assayed, maternal age, smoking (marijuana/cigarettes) and illicit drug/methadone use in pregnancy were examined. For the HIV/HAART group, relationships with CD4+ count and HIV plasma viral load (pVL) near delivery, as well as length of HAART exposure were also examined. Results: The Taq error rate from PCR caused a low signal (mutation) to noise (background) ratio. Therefore, only AC/TG mutations, not induced under our assay conditions, were analysed. No significant difference was found between the percentage of HIV/HAART-exposed infants with AC/TG mutations (N=15/57, 26.3%) and controls (N=10/70, 14.3%) before (p=0.090) or after (p=0.058) controlling for covariates, although a trend was observed. Furthermore, significantly more HIV/HAART-exposed mothers (N=18/42, 42.9%) harboured AC/TG mutations compared to controls (N=7/39, 17.9%) both before (p=0.015) and after (p=0.012) controlling for covariates. AC/TG mutations were more prevalent in HIV/HAART-exposed mothers than in their infants (N=42, 42.9% vs. 23.8% p=0.033), however, this difference disappeared after controlling for covariates (p=0.777). No difference was observed between control mothers and their infants (N=39, both 17.9%). In HIV/HAART-exposed group mothers, only a detectable HIV pVL near delivery predicted AC/TG mutations. Conclusion: A subset of mtDNA mutations can be quantified with the developed assay. HIV/HAART exposure in pregnancy may be associated with increased prevalence of maternal mtDNA mutations. Since mtDNA mutations have been linked with aging and age-associated diseases, this raises concerns about the long-term impact of HAART.
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