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- Title
Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models.
- Authors
Smith, Marie-Soleil R; Mohan, Haneesha; Ajaykumar, Abhinav; Hsieh, Anthony Y Y; Martineau, Lou; Patel, Ronil; Gadawska, Izabella; Sherwood, Christopher; Serghides, Lena; Piret, James M; Côté, Hélène C F
- Abstract
<bold>Background: </bold>Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental.<bold>Methods: </bold>The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice.<bold>Results: </bold>At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested.<bold>Conclusions: </bold>Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, 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 after in utero exposure.
- Subjects
INTEGRASE inhibitors; HUMAN embryonic stem cells; HIV; VIRUS inhibitors; POISONS; LABORATORY mice; HIV integrase inhibitors; PROTEINS; HETEROCYCLIC compounds; RESEARCH funding; ANIMALS; DRUG resistance in microorganisms; HIV infections; PERINATAL death; MICE; PYRIDINE
- Publication
Journal of Infectious Diseases, 2022, Vol 226, Issue 11, p1992
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiac386