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UBC Theses and Dissertations

Cellular and mitochondrial toxicity of integrase strand transfer inhibitors in human embryonic stem cell models Smith, Marie-Soleil Rouleau


Each year, over one million more children are exposed in utero to HIV antiretrovirals (ARVs), yet their safety is often not well characterized during pregnancy. Many ARVs are known to affect mitochondrial function that, if altered during initial stages of embryonic and placental development, could have detrimental consequences for cellular differentiation and early development. Recent studies suggested a concerning association between exposure to the integrase inhibitor (InSTI) dolutegravir (DTG) during early development and increased incidence of neurologic outcomes, such as neural tube defects. As the latter occur within the first four weeks of embryo development, it is crucial to identify the effects of ARVs during the early stages of gestation, on both mitochondrial health and the differentiation of early human embryos. To address this, I sought to characterize and compare the effects of several clinically relevant ARVs in cultured human embryonic stem cell (hESC) models, with respect to cellular and mitochondrial health. I also investigated the effects of ARV exposure on hESC markers of pluripotency, and during their directed germ layer differentiation. I found that even at sub-therapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC cell counts, pluripotency, numerous metrics of mitochondrial health, and dysregulated the expression of genes involved in early differentiation. Notably, first-generation InSTI raltegravir did not induce this hESC toxicity or affect differentiation at any concentration tested. Exposure to some InSTIs at clinically relevant concentrations or even lower can induce adverse effects in hESCs. There are now over 30 ARVs in the HIV therapeutic arsenal but we have little insight into which combination ARV regimens are the most pregnancy-safe. Given the increasingly prevalent use of second-generation InSTIs worldwide, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety following in utero exposure. My study provides crucial pre-clinical information on the relative toxicity of multiple ARVs. This new knowledge can inform future human trials and help guide improved strategies for the treatment of HIV in women of reproductive age.

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