The local environment orchestrates mucosal decidual macrophage differentiation and substantially inhibits HIV-1 replication.
Macrophages from the decidua basalis (dM), the main uterine mucosa during pregnancy, are weakly permissive to HIV-1 infection. Here, we investigated the mechanisms underlying this natural control. We show, by using freshly purified decidual macrophages and ex vivo human decidual explants, that the local decidual environment influences dM differentiation and naturally protects these cells from HIV-1 infection. Interferon (IFN)-γ, present in the decidual tissue, contributes to maintenance of the dM phenotype and restricts HIV-1 infection by mechanisms involving the cyclin-dependent kinase inhibitor p21Cip1/Waf1. We also found that activation of Toll-like receptors 7 and 8 expressed by dM reinforces the low permissivity of dM to HIV-1 by restricting viral replication and inducing secretion of cytokines in the decidual environment, including IFN-γ, that shape dM plasticity. A major challenge for HIV-1 eradication is to control infection of tissue-resident macrophages in the female reproductive tract. Our findings provide clues to the development of novel strategies to prevent HIV-1 macrophage infection.
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.
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El Costa
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.
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Quillay
Université Paris Sud, UMR 1184, Orsay, France.|CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Roses, France.|Inserm, U1184, Center for immunology of viral infections and autoimmune diseases, Fontenay-aux-Roses, France.|Vaccine Research Institute (VRI), Créteil, France.
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Marlin
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.
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Cannou
Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Persistent Viral Infections (PVI) Team, Paris, France.
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Duriez
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.
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Benjelloun
Gynecology-Obstetrics Service, A. Béclère Hospital, AP-HP, Clamart, France.
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de Truchis
Gynecology-Obstetrics Service, Pitié Salpetrière Hospital AP-HP, Paris, France.
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Rahmati
Gynecology-Obstetrics Service, Pitié Salpetrière Hospital AP-HP, Paris, France.
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Ighil
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.
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Barré-Sinoussi
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.
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Nugeyre
Institut Pasteur, Regulation of Retroviral Infection Unit, Paris, France.|Université Paris Sud, UMR 1184, Orsay, France.|CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Roses, France.|Inserm, U1184, Center for immunology of viral infections and autoimmune diseases, Fontenay-aux-Roses, France.
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D002454:Cell Differentiation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003656:Decidua / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D014779:Virus Replication
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D007371:Interferon-gamma