Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

Abstract Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (P...

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Autores principales:	Vaclav Janovec, Jan Hodek, Kamila Clarova, Tomas Hofman, Pavel Dostalik, Jiri Fronek, Jaroslav Chlupac, Laurence Chaperot, Sarah Durand, Thomas F. Baumert, Iva Pichova, Barbora Lubyova, Ivan Hirsch, Jan Weber
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d66559148ab3479e9a9a72c1b20bba42
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spelling	oai:doaj.org-article:d66559148ab3479e9a9a72c1b20bba422021-12-02T16:06:38ZToll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes10.1038/s41598-020-69614-72045-2322https://doaj.org/article/d66559148ab3479e9a9a72c1b20bba422020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-69614-7https://doaj.org/toc/2045-2322Abstract Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.Vaclav JanovecJan HodekKamila ClarovaTomas HofmanPavel DostalikJiri FronekJaroslav ChlupacLaurence ChaperotSarah DurandThomas F. BaumertIva PichovaBarbora LubyovaIvan HirschJan WeberNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vaclav Janovec Jan Hodek Kamila Clarova Tomas Hofman Pavel Dostalik Jiri Fronek Jaroslav Chlupac Laurence Chaperot Sarah Durand Thomas F. Baumert Iva Pichova Barbora Lubyova Ivan Hirsch Jan Weber Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
description	Abstract Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.
format	article
author	Vaclav Janovec Jan Hodek Kamila Clarova Tomas Hofman Pavel Dostalik Jiri Fronek Jaroslav Chlupac Laurence Chaperot Sarah Durand Thomas F. Baumert Iva Pichova Barbora Lubyova Ivan Hirsch Jan Weber
author_facet	Vaclav Janovec Jan Hodek Kamila Clarova Tomas Hofman Pavel Dostalik Jiri Fronek Jaroslav Chlupac Laurence Chaperot Sarah Durand Thomas F. Baumert Iva Pichova Barbora Lubyova Ivan Hirsch Jan Weber
author_sort	Vaclav Janovec
title	Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
title_short	Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
title_full	Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
title_fullStr	Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
title_full_unstemmed	Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes
title_sort	toll-like receptor dual-acting agonists are potent inducers of pbmc-produced cytokines that inhibit hepatitis b virus production in primary human hepatocytes
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/d66559148ab3479e9a9a72c1b20bba42
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Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

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