2. Academic Validation
  3. Second-generation HIV integrase inhibitors induce differentiation dysregulation and exert toxic effects in human embryonic stem cell and mouse models

Second-generation HIV integrase inhibitors induce differentiation dysregulation and exert toxic effects in human embryonic stem cell and mouse models

  • J Infect Dis. 2022 Sep 19;jiac386. doi: 10.1093/infdis/jiac386.
Marie Soleil R Smith 1 2,  Haneesha Mohan 3,  Abhinav Ajaykumar 1 2,  Anthony Y Y Hsieh 1 2,  Lou Martineau 1,  Ronil Patel 1,  Izabella Gadawska 1 2,  Christopher Sherwood 4,  Lena Serghides 3 5 6,  James M Piret 4 7 8,  Hélène C F Côté 1 2 9
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada V6T 1Z7.
  • 2 Centre for Blood Research, University of British Columbia, Vancouver, Canada V6T 1Z3.
  • 3 Toronto General Hospital Research Institute, University Health Network, Toronto, Canada M5G 1L7.
  • 4 Michael Smith Laboratories, University of British Columbia, Vancouver, Canada V6T 1Z4.
  • 5 Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A8.
  • 6 Women's College Research Institute, Toronto, Canada M5G 1N8.
  • 7 Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, Canada V6T 1Z3.
  • 8 School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada V6T 1Z3.
  • 9 Women's Health Research Institute, Vancouver, Canada V6H 2N9.
PMID: 36124861 DOI: 10.1093/infdis/jiac386
Abstract

Background: Each year, approximately 1.1 million children are exposed in utero to HIV 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 inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental.

Methods: The effects of InSTIs on two human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. Additionally, fetal resorptions following exposure to InSTIs from conception were analyzed in pregnant mice.

Results: At sub-therapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts, pluripotency, and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. Notably, first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested.

Conclusions: Exposure to some InSTIs, even at sub-therapeutic 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 following in utero exposure.

Keywords

HIV; InSTI; antiretroviral; hESC; integrase inhibitor; mice; pregnancy; toxicity.

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