Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapyin utero

Abstract

The use of combination antiretroviral therapy (cART) to prevent HIV mother-to-child transmission during pregnancy and delivery is generally considered safe. However, vigilant assessment of potential risks of these agents remains warranted. Epigenetic changes including DNA methylation are considered potential mechanisms linking the in utero environment with long-term health outcomes. Few studies have examined the epigenetic effects of prenatal exposure to pharmaceutical agents, including antiretroviral therapies, on children. In this study, we examined the methylation status of the LINE-1 and ALU-Yb8 repetitive elements as markers of global DNA methylation alteration in peripheral blood mononuclear cells obtained from newborns participating in the Pediatric HIV/AIDS Cohort Study SMARTT cohort of HIV-exposed, cART-exposed uninfected infants compared to a historical cohort of HIV-exposed, antiretroviral-unexposed infants from the Women and Infants Transmission Study Cohort. In linear regression models controlling for potential confounders, we found the adjusted mean difference of AluYb8 methylation of the cART-exposed compared to the -unexposed was -0.568 (95% CI: -1.023, -0.149) and for LINE-1 methylation was -1.359 (95% CI: -1.860, -0.857). Among those exposed to cART, subjects treated with atazanavir (ATV), compared to those on other treatments, had less AluYb8 methylation (-0.524, 95% CI: -0.025, -1.024). Overall, these results suggest a small but statistically significant reduction in the methylation of these repetitive elements in an HIV-exposed, cART-exposed cohort compared to an HIV-exposed, cART-unexposed historic cohort. The potential long-term implications of these differences are worthy of further examination.

Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design

“…31 Other mechanisms of toxicity, such as epigenetic effects and metabolic toxicities, may also play a role. 38–40 While previous animal studies and case reports have noted potential associations of in utero efavirenz exposure with neural tube defects or other neurological outcomes, 31–33 we observed only slightly elevated risk of neurological case (9.8% for EFV-exposed vs. 6.0% for EFV-unexposed) which did not attain statistical significance.…”

“…However, we evaluated multiple domains of interest which could reflect mitochondrial dysfunction, epigenetic effects, or other mechanisms of toxicity related to intrauterine exposures. 38–40 A potential limitation of our trigger-based approach is that it may have missed certain AEs, and all domains were treated equally which may not reflect the relative clinical significance of toxicities across different domains. In addition, ARV drugs could have opposing effects on different domains, which would tend to obscure associations with overall case status.…”

Immunoassay and molecular methods to investigate DNA methylation changes in peripheral blood mononuclear cells in HIV infected patients on cART

“…These findings are supported by previous studies that observed an accumulation of methylation in integrated viral genomes, in long-term-treated HIV patients 22 or a hipomethylating effect of atazanavir, a protease inhibitor, on AluYb8 repetitive element in infants exposed to ART in utero 26 .…”

Prenatal exposures and DNA methylation in newborns: a pilot study in Durban, South Africa

“…Additional concepts enriched with an FDR of 10% include processes involved in viral processing and regulation, and this may be a result of treatment exposure or a response to viral exposure. The few previous studies examining the impact of HIV and maternal antiviral therapies on the neonatal epigenome suggest that antiviral treatment and not infection itself is the driver of change (50,51). Heterochromatin differences were observed in lymphocytes from children with prenatal nucleoside reverse transcriptase inhibitor (NRTI) exposure compared with children without NRTI exposure regardless of maternal HIV status (51).…”

“…Heterochromatin differences were observed in lymphocytes from children with prenatal nucleoside reverse transcriptase inhibitor (NRTI) exposure compared with children without NRTI exposure regardless of maternal HIV status (51). Likewise, maternal anti-viral therapy was associated with DNA hypomethylation at repetitive elements, a global marker, in newborn peripheral blood mononuclear cells (PBMCs) compared with newborns from untreated HIV-positive mothers (50). Of the eight HIV positive mothers in the MACE cohort, at the time of birth seven took Nevaripine (a non-NRTI), one additionally took azidothymidine (a NRTI), and one was untreated.…”