Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function
Protease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those func...
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doaj-2476b3f6dd8a44ac865eceb03d72c4812021-01-13T00:02:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-012268368310.3390/ijms22020683Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine FunctionCamille Fraichard0Fidéline Bonnet-Serrano1Christelle Laguillier-Morizot2Marylise Hebert-Schuster3René Lai-Kuen4Jeanne Sibiude5Thierry Fournier6Marie Cohen7Jean Guibourdenche8INSERM UMR-S 1139, Faculté de Pharmacie, Université de Paris, 75006 Paris, FranceService d’Hormonologie, CHU Cochin, HUPC, AP-HP, 75014 Paris, FranceINSERM UMR-S 1139, Faculté de Pharmacie, Université de Paris, 75006 Paris, FranceService de Gynécologie-Obstétrique, Faculté de Médecine, Université de Genève, 1206 Genève, SuisseINSERM UMS 025—CNRS UMS 3612, Faculté de Pharmacie, Université de Paris, 75006 Paris, FranceService de Gynécologie-Obstétrique, CHU Louis Mourier, HUPN, AP-HP, 92700 Colombes, FranceINSERM UMR-S 1139, Faculté de Pharmacie, Université de Paris, 75006 Paris, FranceService de Gynécologie-Obstétrique, Faculté de Médecine, Université de Genève, 1206 Genève, SuisseINSERM UMR-S 1139, Faculté de Pharmacie, Université de Paris, 75006 Paris, FranceProtease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those functions are ensured by the villous trophoblast and are mainly regulated by the Unfolded Protein Response (UPR) pathway and mitochondria. We investigated, in vitro, if PI impair hCG and P4 production and the potential intracellular mechanisms involved. Term villous cytotrophoblast (VCT) were cultured with or without RTV or LPV from 6 to 48 h. VCT differentiation into syncytiotrophoblast (ST) was followed measuring hCG and P4 secretion. We evaluated the expression of P4 synthesis partners (Metastatic Lymph Node 64 (MLN64), cholesterol side-chain cleavage (P450SCC), Hydroxy-delta-5-Steroid Dehydrogenase and 3 Beta-and steroid delta-isomerase 1 (HSD3B1)), of mitochondrial pro-fusion factors (Mitofusin 2 (Mfn2), Optic Atrophy 1 (OPA1)) and of UPR factors (Glucose-Regulated Protein 78 (GRP78), Activating Transcription Factor 4 (ATF4), Activating Transcription Factor 6 (ATF6), spliced X-box Binding Protein 1 (sXBP1)). RTV had no significant effect on hCG and P4 secretion, whereas lopinavir significantly decreased both secretions. LPV also decreased P450SCC and HSD3B1 expression, whereas it increased Mfn2, GRP78 and sXBP1 expression in ST. RTV has no effect on the endocrine placenta. LPV impairs both villous trophoblast differentiation and P4 production. It is likely to act via mitochondrial fusion and UPR pathway activation. These trophoblastic alterations may end in decreased P4 levels in maternal circulation, inducing prematurity.https://www.mdpi.com/1422-0067/22/2/683human placentalopinavirprogesteronemitochondriaMfn2UPR |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Camille Fraichard Fidéline Bonnet-Serrano Christelle Laguillier-Morizot Marylise Hebert-Schuster René Lai-Kuen Jeanne Sibiude Thierry Fournier Marie Cohen Jean Guibourdenche |
spellingShingle |
Camille Fraichard Fidéline Bonnet-Serrano Christelle Laguillier-Morizot Marylise Hebert-Schuster René Lai-Kuen Jeanne Sibiude Thierry Fournier Marie Cohen Jean Guibourdenche Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function International Journal of Molecular Sciences human placenta lopinavir progesterone mitochondria Mfn2 UPR |
author_facet |
Camille Fraichard Fidéline Bonnet-Serrano Christelle Laguillier-Morizot Marylise Hebert-Schuster René Lai-Kuen Jeanne Sibiude Thierry Fournier Marie Cohen Jean Guibourdenche |
author_sort |
Camille Fraichard |
title |
Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function |
title_short |
Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function |
title_full |
Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function |
title_fullStr |
Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function |
title_full_unstemmed |
Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function |
title_sort |
protease inhibitor anti-hiv, lopinavir, impairs placental endocrine function |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-01-01 |
description |
Protease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those functions are ensured by the villous trophoblast and are mainly regulated by the Unfolded Protein Response (UPR) pathway and mitochondria. We investigated, in vitro, if PI impair hCG and P4 production and the potential intracellular mechanisms involved. Term villous cytotrophoblast (VCT) were cultured with or without RTV or LPV from 6 to 48 h. VCT differentiation into syncytiotrophoblast (ST) was followed measuring hCG and P4 secretion. We evaluated the expression of P4 synthesis partners (Metastatic Lymph Node 64 (MLN64), cholesterol side-chain cleavage (P450SCC), Hydroxy-delta-5-Steroid Dehydrogenase and 3 Beta-and steroid delta-isomerase 1 (HSD3B1)), of mitochondrial pro-fusion factors (Mitofusin 2 (Mfn2), Optic Atrophy 1 (OPA1)) and of UPR factors (Glucose-Regulated Protein 78 (GRP78), Activating Transcription Factor 4 (ATF4), Activating Transcription Factor 6 (ATF6), spliced X-box Binding Protein 1 (sXBP1)). RTV had no significant effect on hCG and P4 secretion, whereas lopinavir significantly decreased both secretions. LPV also decreased P450SCC and HSD3B1 expression, whereas it increased Mfn2, GRP78 and sXBP1 expression in ST. RTV has no effect on the endocrine placenta. LPV impairs both villous trophoblast differentiation and P4 production. It is likely to act via mitochondrial fusion and UPR pathway activation. These trophoblastic alterations may end in decreased P4 levels in maternal circulation, inducing prematurity. |
topic |
human placenta lopinavir progesterone mitochondria Mfn2 UPR |
url |
https://www.mdpi.com/1422-0067/22/2/683 |
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