Second-Generation Human Immunodeficiency Virus Integrase Inhibitors Induce Differentiation Dysregulation and Exert Toxic Effects in Human Embryonic Stem Cell and Mouse Models.
Animals
Female
Humans
Mice
Pregnancy
Drug Resistance, Viral
/ genetics
Fetal Resorption
/ chemically induced
Heterocyclic Compounds, 3-Ring
/ toxicity
Heterocyclic Compounds, 4 or More Rings
/ pharmacology
HIV Infections
/ drug therapy
HIV Integrase Inhibitors
/ toxicity
Human Embryonic Stem Cells
/ metabolism
Pyridones
/ therapeutic use
Raltegravir Potassium
/ toxicity
Infant, Newborn
Maternal Exposure
HIV
antiretroviral
hESC
integrase inhibitor
pregnancy
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
28 11 2022
28 11 2022
Historique:
received:
19
07
2022
accepted:
16
09
2022
pubmed:
21
9
2022
medline:
1
12
2022
entrez:
20
9
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Identifiants
pubmed: 36124861
pii: 6704757
doi: 10.1093/infdis/jiac386
pmc: PMC10205620
doi:
Substances chimiques
bictegravir
8GB79LOJ07
Heterocyclic Compounds, 3-Ring
0
Heterocyclic Compounds, 4 or More Rings
0
HIV Integrase Inhibitors
0
Pyridones
0
Raltegravir Potassium
43Y000U234
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1992-2001Subventions
Organisme : NICHD NIH HHS
ID : R01 HD104553
Pays : United States
Organisme : NICHD NIH HHS
ID : R01HD104553
Pays : United States
Organisme : CIHR
ID : PJT-156007
Pays : Canada
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Déclaration de conflit d'intérêts
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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