Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

ABSTRACT Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) and may serve as a viral reservoir during antiretroviral therapy (ART). Their susceptibility to HIV-1 infection is subject to variations from permissiveness to resistance depending on their origin, tissue localization,...

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Autores principales:	Robert Lodge, Nicolas Bellini, Mélanie Laporte, Syim Salahuddin, Jean-Pierre Routy, Petronela Ancuta, Cecilia T. Costiniuk, Mohammad-Ali Jenabian, Éric A. Cohen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	alveolar macrophage CCR5 CD4 colon macrophage HIV reservoir IL-1β Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bf3c9c672de24376b80f6cc1733e60a9
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spelling	oai:doaj.org-article:bf3c9c672de24376b80f6cc1733e60a92021-11-15T16:19:09ZInterleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 10710.1128/mBio.02314-202150-7511https://doaj.org/article/bf3c9c672de24376b80f6cc1733e60a92020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02314-20https://doaj.org/toc/2150-7511ABSTRACT Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) and may serve as a viral reservoir during antiretroviral therapy (ART). Their susceptibility to HIV-1 infection is subject to variations from permissiveness to resistance depending on their origin, tissue localization, and polarization profile. This is in part due to the expression of regulatory microRNAs. Here, we identify two microRNA paralogs, microRNA 103 (miR-103) and miR-107, as regulators of CCR5 expression that are upregulated in noninfected bystander cells of HIV-1-infected-monocyte-derived macrophage (MDM) cultures. Transfection of microRNA 103 mimics in MDMs reduced CCR5 expression levels and inhibited CCR5-dependent HIV-1 entry, whereas the corresponding antagomirs enhanced virus spread in HIV-infected MDMs. Treatment of MDMs with interleukin-1β (IL-1β) enhanced microRNA 103 expression, a condition that we found contributed to the reduction of CCR5 mRNA in IL-1β-exposed MDMs. Interestingly, we show that the induction of miR-103/107 expression is part of a tumor suppressor p53 response triggered by secreted IL-1β that renders macrophages refractory to HIV-1 entry. In a more physiological context, the levels of microRNAs 103 and 107 were found enriched in tissue-resident colon macrophages of healthy donors and alveolar macrophages of individuals under antiretroviral therapy, conceivably contributing to their relative resistance to HIV-1 infection. Overall, these findings highlight the role of p53 in enforcing proinflammatory antiviral responses in macrophages, at least in part, through miR-103/107-mediated downmodulation of CCR5 expression and HIV-1 entry. IMPORTANCE Macrophages are heterogeneous immune cells that display varying susceptibilities to HIV-1 infection, in part due to the expression of small noncoding microRNAs involved in the posttranscriptional regulation of gene expression and silencing. Here, we identify microRNAs 103 and 107 as important p53-regulated effectors of the antiviral response triggered by the proinflammatory cytokine IL-1β in macrophages. These microRNAs, which are enriched in colon macrophages of healthy donors and alveolar macrophages of HIV-infected individuals under antiretroviral therapy, act as inhibitors of HIV-1 entry through their capacity to downregulate the CCR5 coreceptor. These results highlight the important role played by miR-103/107 in modulating CCR5 expression and HIV-1 entry in macrophages. They further underscore a distinct function of the tumor suppressor p53 in enforcing proinflammatory antiviral responses in macrophages, thus providing insight into a cellular pathway that could be targeted to limit the establishment of viral reservoirs in these cells.Robert LodgeNicolas BelliniMélanie LaporteSyim SalahuddinJean-Pierre RoutyPetronela AncutaCecilia T. CostiniukMohammad-Ali JenabianÉric A. CohenAmerican Society for Microbiologyarticlealveolar macrophageCCR5CD4colon macrophageHIV reservoirIL-1βMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	alveolar macrophage CCR5 CD4 colon macrophage HIV reservoir IL-1β Microbiology QR1-502
spellingShingle	alveolar macrophage CCR5 CD4 colon macrophage HIV reservoir IL-1β Microbiology QR1-502 Robert Lodge Nicolas Bellini Mélanie Laporte Syim Salahuddin Jean-Pierre Routy Petronela Ancuta Cecilia T. Costiniuk Mohammad-Ali Jenabian Éric A. Cohen Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
description	ABSTRACT Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) and may serve as a viral reservoir during antiretroviral therapy (ART). Their susceptibility to HIV-1 infection is subject to variations from permissiveness to resistance depending on their origin, tissue localization, and polarization profile. This is in part due to the expression of regulatory microRNAs. Here, we identify two microRNA paralogs, microRNA 103 (miR-103) and miR-107, as regulators of CCR5 expression that are upregulated in noninfected bystander cells of HIV-1-infected-monocyte-derived macrophage (MDM) cultures. Transfection of microRNA 103 mimics in MDMs reduced CCR5 expression levels and inhibited CCR5-dependent HIV-1 entry, whereas the corresponding antagomirs enhanced virus spread in HIV-infected MDMs. Treatment of MDMs with interleukin-1β (IL-1β) enhanced microRNA 103 expression, a condition that we found contributed to the reduction of CCR5 mRNA in IL-1β-exposed MDMs. Interestingly, we show that the induction of miR-103/107 expression is part of a tumor suppressor p53 response triggered by secreted IL-1β that renders macrophages refractory to HIV-1 entry. In a more physiological context, the levels of microRNAs 103 and 107 were found enriched in tissue-resident colon macrophages of healthy donors and alveolar macrophages of individuals under antiretroviral therapy, conceivably contributing to their relative resistance to HIV-1 infection. Overall, these findings highlight the role of p53 in enforcing proinflammatory antiviral responses in macrophages, at least in part, through miR-103/107-mediated downmodulation of CCR5 expression and HIV-1 entry. IMPORTANCE Macrophages are heterogeneous immune cells that display varying susceptibilities to HIV-1 infection, in part due to the expression of small noncoding microRNAs involved in the posttranscriptional regulation of gene expression and silencing. Here, we identify microRNAs 103 and 107 as important p53-regulated effectors of the antiviral response triggered by the proinflammatory cytokine IL-1β in macrophages. These microRNAs, which are enriched in colon macrophages of healthy donors and alveolar macrophages of HIV-infected individuals under antiretroviral therapy, act as inhibitors of HIV-1 entry through their capacity to downregulate the CCR5 coreceptor. These results highlight the important role played by miR-103/107 in modulating CCR5 expression and HIV-1 entry in macrophages. They further underscore a distinct function of the tumor suppressor p53 in enforcing proinflammatory antiviral responses in macrophages, thus providing insight into a cellular pathway that could be targeted to limit the establishment of viral reservoirs in these cells.
format	article
author	Robert Lodge Nicolas Bellini Mélanie Laporte Syim Salahuddin Jean-Pierre Routy Petronela Ancuta Cecilia T. Costiniuk Mohammad-Ali Jenabian Éric A. Cohen
author_facet	Robert Lodge Nicolas Bellini Mélanie Laporte Syim Salahuddin Jean-Pierre Routy Petronela Ancuta Cecilia T. Costiniuk Mohammad-Ali Jenabian Éric A. Cohen
author_sort	Robert Lodge
title	Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
title_short	Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
title_full	Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
title_fullStr	Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
title_full_unstemmed	Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107
title_sort	interleukin-1β triggers p53-mediated downmodulation of ccr5 and hiv-1 entry in macrophages through micrornas 103 and 107
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/bf3c9c672de24376b80f6cc1733e60a9
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Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

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