{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T20:12:25Z","timestamp":1762459945686,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["17198"],"award-info":[{"award-number":["17198"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22020683","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T14:28:53Z","timestamp":1610461733000},"page":"683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function"],"prefix":"10.3390","volume":"22","author":[{"given":"Camille","family":"Fraichard","sequence":"first","affiliation":[{"name":"INSERM UMR-S 1139, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6628-8807","authenticated-orcid":false,"given":"Fid\u00e9line","family":"Bonnet-Serrano","sequence":"additional","affiliation":[{"name":"Service d\u2019Hormonologie, CHU Cochin, HUPC, AP-HP, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christelle","family":"Laguillier-Morizot","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1139, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 75006 Paris, France"},{"name":"Service d\u2019Hormonologie, CHU Cochin, HUPC, AP-HP, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8221-4023","authenticated-orcid":false,"given":"Marylise","family":"Hebert-Schuster","sequence":"additional","affiliation":[{"name":"Service de Gyn\u00e9cologie-Obst\u00e9trique, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Gen\u00e8ve, 1206 Gen\u00e8ve, Suisse"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9","family":"Lai-Kuen","sequence":"additional","affiliation":[{"name":"INSERM UMS 025\u2014CNRS UMS 3612, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanne","family":"Sibiude","sequence":"additional","affiliation":[{"name":"Service de Gyn\u00e9cologie-Obst\u00e9trique, CHU Louis Mourier, HUPN, AP-HP, 92700 Colombes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thierry","family":"Fournier","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1139, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Cohen","sequence":"additional","affiliation":[{"name":"Service de Gyn\u00e9cologie-Obst\u00e9trique, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Gen\u00e8ve, 1206 Gen\u00e8ve, Suisse"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Guibourdenche","sequence":"additional","affiliation":[{"name":"INSERM UMR-S 1139, Facult\u00e9 de Pharmacie, Universit\u00e9 de Paris, 75006 Paris, France"},{"name":"Service d\u2019Hormonologie, CHU Cochin, HUPC, AP-HP, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2016). 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