Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function

Article Article scientifique Article Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function eng 2021 author Fraichard Camille author Bonnet-Serrano Fidéline author Laguillier-Morizot Christelle author Schuster Hebert Marylise 887793 author Lai-Kuen René author Sibiude Jeanne author Fournier Thierry author Cohen Marie-Benoîte 0000-0003-4621-5464 135615 author Guibourdenche Jean 683 10.3390/ijms22020683 33445576 1661-6596 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827556/ 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. Human placenta Lopinavir Progesterone Mitochondria Mfn2 UPR IRE1α Dewey 618 58 Département de pédiatrie, gynécologie et obstétrique 223 false 584 Laboratoire de biologie des tumeurs gynécologiques et du développement 927 International Journal of Molecular Sciences 22 2 208d4748-596f-4575-bd23-1edbc67f15b1 Article (Published version) Public ijms-22-00683.pdf 7258900 application/pdf CC BY openAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function	International Journal of Molecular Sciences			2021	391	178

Archive ouverte UNIGE

Schuster Hebert, Marylise