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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| Format: | Article |
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Nature Portfolio
2020-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-69614-7 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T17:30:57Z |
| format | Article |
| id | doaj.art-d66559148ab3479e9a9a72c1b20bba42 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T17:30:57Z |
| publishDate | 2020-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-d66559148ab3479e9a9a72c1b20bba422022-12-21T23:37:03ZengNature PortfolioScientific Reports2045-23222020-07-0110111110.1038/s41598-020-69614-7Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytesVaclav Janovec0Jan Hodek1Kamila Clarova2Tomas Hofman3Pavel Dostalik4Jiri Fronek5Jaroslav Chlupac6Laurence Chaperot7Sarah Durand8Thomas F. Baumert9Iva Pichova10Barbora Lubyova11Ivan Hirsch12Jan Weber13Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEVIOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of ScienceIOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of ScienceDepartment of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEVDepartment of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEVTransplantation Surgery Department, Institute for Clinical and Experimental MedicineTransplantation Surgery Department, Institute for Clinical and Experimental MedicineCNRS UMR5309, Inserm U1209, CHU Grenoble Alpes, IAB, EFS, Université Grenoble AlpesInserm, Institut de Recherche Sur Les Maladies Virales Et Hepatiques UMRS 1110, Universite de StrasbourgInserm, Institut de Recherche Sur Les Maladies Virales Et Hepatiques UMRS 1110, Universite de StrasbourgIOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of ScienceIOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of ScienceDepartment of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEVIOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of ScienceAbstract 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.https://doi.org/10.1038/s41598-020-69614-7 |
| spellingShingle | 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 Scientific Reports |
| 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_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_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_sort | toll like receptor dual acting agonists are potent inducers of pbmc produced cytokines that inhibit hepatitis b virus production in primary human hepatocytes |
| url | https://doi.org/10.1038/s41598-020-69614-7 |
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