DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection
1 INSERM, Unit 871, F-69424 Lyon, France 2 Université Lyon 1, IFR62, F-69008 Lyon, France 3 Ecole Nationale Vétérinaire de Lyon, F-69280 Marcy l'Etoile, France 4 Pathology Department, Marcel Mérieux Laboratory, F-69007 Lyon, France 5 Hospices Civiles de Lyon, Department of Hepatology, Hotel-Die...
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| Veröffentlicht in: | Journal of general virology 2008-05, Vol.89 (5), p.1192-1201 |
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| creator | Thermet, Alexandre Buronfosse, Thierry Werle-Lapostolle, Bettina Chevallier, Michele Pradat, Pierre Trepo, Christian Zoulim, Fabien Cova, Lucyna |
| description | 1 INSERM, Unit 871, F-69424 Lyon, France
2 Université Lyon 1, IFR62, F-69008 Lyon, France
3 Ecole Nationale Vétérinaire de Lyon, F-69280 Marcy l'Etoile, France
4 Pathology Department, Marcel Mérieux Laboratory, F-69007 Lyon, France
5 Hospices Civiles de Lyon, Department of Hepatology, Hotel-Dieu, F-69002 Lyon, France
Correspondence Lucyna Cova cova{at}lyon.inserm.fr
This study used a duck hepatitis B virus (DHBV) model to evaluate whether a novel DNA vaccination protocol alone or associated with antiviral (lamivudine) treatment was able to clear the intrahepatic covalently closed, circular viral DNA (cccDNA) pool responsible for persistence of infection. DHBV carriers received DNA vaccine (on weeks 6, 10, 13, 14, 28 and 35) targeting the large envelope and/or core proteins alone or combined with lamivudine treatment (on weeks 1–8) or lamivudine monotherapy. After 10 months of follow-up, a dramatic decrease in viraemia and liver DHBV cccDNA (below 0.08 cccDNA copies per cell) was observed in 9/30 ducks (30 %) receiving DNA mono- or combination therapy, compared with 0/12 (0 %) from lamivudine monotherapy or the control groups, suggesting a significant antiviral effect of DNA immunization. However, association with the drug did not significantly improve DHBV DNA vaccine efficacy (33 % cccDNA clearance for the combination vs 27 % for DNA monotherapy), probably due to the low antiviral potency of lamivudine in the duck model. Seroconversion to anti-preS was observed in 6/9 (67 %) ducks showing cccDNA clearance, compared with 1/28 (3.6 %) without clearance, suggesting a significant correlation ( P |
| doi_str_mv | 10.1099/vir.0.83583-0 |
| format | Article |
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2 Université Lyon 1, IFR62, F-69008 Lyon, France
3 Ecole Nationale Vétérinaire de Lyon, F-69280 Marcy l'Etoile, France
4 Pathology Department, Marcel Mérieux Laboratory, F-69007 Lyon, France
5 Hospices Civiles de Lyon, Department of Hepatology, Hotel-Dieu, F-69002 Lyon, France
Correspondence Lucyna Cova cova{at}lyon.inserm.fr
This study used a duck hepatitis B virus (DHBV) model to evaluate whether a novel DNA vaccination protocol alone or associated with antiviral (lamivudine) treatment was able to clear the intrahepatic covalently closed, circular viral DNA (cccDNA) pool responsible for persistence of infection. DHBV carriers received DNA vaccine (on weeks 6, 10, 13, 14, 28 and 35) targeting the large envelope and/or core proteins alone or combined with lamivudine treatment (on weeks 1–8) or lamivudine monotherapy. After 10 months of follow-up, a dramatic decrease in viraemia and liver DHBV cccDNA (below 0.08 cccDNA copies per cell) was observed in 9/30 ducks (30 %) receiving DNA mono- or combination therapy, compared with 0/12 (0 %) from lamivudine monotherapy or the control groups, suggesting a significant antiviral effect of DNA immunization. However, association with the drug did not significantly improve DHBV DNA vaccine efficacy (33 % cccDNA clearance for the combination vs 27 % for DNA monotherapy), probably due to the low antiviral potency of lamivudine in the duck model. Seroconversion to anti-preS was observed in 6/9 (67 %) ducks showing cccDNA clearance, compared with 1/28 (3.6 %) without clearance, suggesting a significant correlation ( P <0.001) between humoral response restoration and cccDNA elimination. Importantly, an early (weeks 10–12) drop in viraemia was observed in seroconverted animals, and virus replication did not rebound following the cessation of immunotherapy, indicating a sustained effect. This study provides the first evidence that therapeutic DNA vaccination is able to enhance hepadnaviral cccDNA clearance, which is tightly associated with a break in humoral immune tolerance. These results also highlight the importance of antiviral drug potency and an effective DNA immunization protocol for the design of therapeutic vaccines against chronic hepatitis B.</description><identifier>ISSN: 0022-1317</identifier><identifier>EISSN: 1465-2099</identifier><identifier>DOI: 10.1099/vir.0.83583-0</identifier><identifier>PMID: 18420797</identifier><identifier>CODEN: JGVIAY</identifier><language>eng</language><publisher>Reading: Soc General Microbiol</publisher><subject>Animals ; Biological and medical sciences ; DNA, Viral - genetics ; Duck hepatitis B virus ; Ducks ; Follow-Up Studies ; Fundamental and applied biological sciences. Psychology ; Hepadnaviridae Infections - immunology ; Hepatitis B Antibodies - blood ; Hepatitis B Core Antigens - genetics ; Hepatitis B Core Antigens - immunology ; Hepatitis B virus ; Hepatitis B Virus, Duck - genetics ; Hepatitis B Virus, Duck - immunology ; Hepatitis, Viral, Animal - immunology ; Immune Tolerance ; Lamivudine - therapeutic use ; Liver - virology ; Microbiology ; Miscellaneous ; Vaccines, DNA - genetics ; Vaccines, DNA - immunology ; Viral Envelope Proteins - genetics ; Viral Envelope Proteins - immunology ; Viremia ; Virology</subject><ispartof>Journal of general virology, 2008-05, Vol.89 (5), p.1192-1201</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-2ed5e9225fb1b0ca9c1ec88041d482972c2a3904d173a8c8bf4cf50ab47b98eb3</citedby><cites>FETCH-LOGICAL-c424t-2ed5e9225fb1b0ca9c1ec88041d482972c2a3904d173a8c8bf4cf50ab47b98eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,3748,3749,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20291325$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18420797$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thermet, Alexandre</creatorcontrib><creatorcontrib>Buronfosse, Thierry</creatorcontrib><creatorcontrib>Werle-Lapostolle, Bettina</creatorcontrib><creatorcontrib>Chevallier, Michele</creatorcontrib><creatorcontrib>Pradat, Pierre</creatorcontrib><creatorcontrib>Trepo, Christian</creatorcontrib><creatorcontrib>Zoulim, Fabien</creatorcontrib><creatorcontrib>Cova, Lucyna</creatorcontrib><title>DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection</title><title>Journal of general virology</title><addtitle>J Gen Virol</addtitle><description>1 INSERM, Unit 871, F-69424 Lyon, France
2 Université Lyon 1, IFR62, F-69008 Lyon, France
3 Ecole Nationale Vétérinaire de Lyon, F-69280 Marcy l'Etoile, France
4 Pathology Department, Marcel Mérieux Laboratory, F-69007 Lyon, France
5 Hospices Civiles de Lyon, Department of Hepatology, Hotel-Dieu, F-69002 Lyon, France
Correspondence Lucyna Cova cova{at}lyon.inserm.fr
This study used a duck hepatitis B virus (DHBV) model to evaluate whether a novel DNA vaccination protocol alone or associated with antiviral (lamivudine) treatment was able to clear the intrahepatic covalently closed, circular viral DNA (cccDNA) pool responsible for persistence of infection. DHBV carriers received DNA vaccine (on weeks 6, 10, 13, 14, 28 and 35) targeting the large envelope and/or core proteins alone or combined with lamivudine treatment (on weeks 1–8) or lamivudine monotherapy. After 10 months of follow-up, a dramatic decrease in viraemia and liver DHBV cccDNA (below 0.08 cccDNA copies per cell) was observed in 9/30 ducks (30 %) receiving DNA mono- or combination therapy, compared with 0/12 (0 %) from lamivudine monotherapy or the control groups, suggesting a significant antiviral effect of DNA immunization. However, association with the drug did not significantly improve DHBV DNA vaccine efficacy (33 % cccDNA clearance for the combination vs 27 % for DNA monotherapy), probably due to the low antiviral potency of lamivudine in the duck model. Seroconversion to anti-preS was observed in 6/9 (67 %) ducks showing cccDNA clearance, compared with 1/28 (3.6 %) without clearance, suggesting a significant correlation ( P <0.001) between humoral response restoration and cccDNA elimination. Importantly, an early (weeks 10–12) drop in viraemia was observed in seroconverted animals, and virus replication did not rebound following the cessation of immunotherapy, indicating a sustained effect. This study provides the first evidence that therapeutic DNA vaccination is able to enhance hepadnaviral cccDNA clearance, which is tightly associated with a break in humoral immune tolerance. These results also highlight the importance of antiviral drug potency and an effective DNA immunization protocol for the design of therapeutic vaccines against chronic hepatitis B.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>DNA, Viral - genetics</subject><subject>Duck hepatitis B virus</subject><subject>Ducks</subject><subject>Follow-Up Studies</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hepadnaviridae Infections - immunology</subject><subject>Hepatitis B Antibodies - blood</subject><subject>Hepatitis B Core Antigens - genetics</subject><subject>Hepatitis B Core Antigens - immunology</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B Virus, Duck - genetics</subject><subject>Hepatitis B Virus, Duck - immunology</subject><subject>Hepatitis, Viral, Animal - immunology</subject><subject>Immune Tolerance</subject><subject>Lamivudine - therapeutic use</subject><subject>Liver - virology</subject><subject>Microbiology</subject><subject>Miscellaneous</subject><subject>Vaccines, DNA - genetics</subject><subject>Vaccines, DNA - immunology</subject><subject>Viral Envelope Proteins - genetics</subject><subject>Viral Envelope Proteins - immunology</subject><subject>Viremia</subject><subject>Virology</subject><issn>0022-1317</issn><issn>1465-2099</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxSMEotvCkSvyBdRLFtuxN_GxlL9SBRc4W85k0pjG9mI7W_HF-Hw47AJHTh7r_TTzZl5VPWN0y6hSrw42bum2a2TX1PRBtWFiJ2telIfVhlLOa9aw9qw6T-kbpUwI2T6uzlgnOG1Vu6l-vvl0RQ4GwHqTbfDEegLB9X--IRIfMrm3eSKzcfawDNYjyRFNdugz6Ut1l8i0uBDNTKxzy6qHGaPxgMT4gaCf1joRAFjnwYzmqJZpeUIyLHBHXBhwJmEkMMXgLZAJ98VEtom8JmXNJRV8RFh9PakejWZO-PT0XlRf3739cv2hvvn8_uP11U0NgotccxwkKs7l2LOeglHAELqOCjaIjquWAzeNomJgbWM66PpRwCip6UXbqw775qJ6eey7j-H7gilrZxPgPBuPYUl6pxiTSsr_gkztlFBKFbA-ghBDShFHvY_WmfhDM6rXRHVZVVP9O1FNC__81HjpHQ7_6FOEBXhxAkwCM4_rYW36y3HKFWv46vDyyE32drq3EfUtemeLjd6GdWintNSMKd78AkdAu4o</recordid><startdate>20080501</startdate><enddate>20080501</enddate><creator>Thermet, Alexandre</creator><creator>Buronfosse, Thierry</creator><creator>Werle-Lapostolle, Bettina</creator><creator>Chevallier, Michele</creator><creator>Pradat, Pierre</creator><creator>Trepo, Christian</creator><creator>Zoulim, Fabien</creator><creator>Cova, Lucyna</creator><general>Soc General Microbiol</general><general>Society for General Microbiology</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20080501</creationdate><title>DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection</title><author>Thermet, Alexandre ; Buronfosse, Thierry ; Werle-Lapostolle, Bettina ; Chevallier, Michele ; Pradat, Pierre ; Trepo, Christian ; Zoulim, Fabien ; Cova, Lucyna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-2ed5e9225fb1b0ca9c1ec88041d482972c2a3904d173a8c8bf4cf50ab47b98eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>DNA, Viral - genetics</topic><topic>Duck hepatitis B virus</topic><topic>Ducks</topic><topic>Follow-Up Studies</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hepadnaviridae Infections - immunology</topic><topic>Hepatitis B Antibodies - blood</topic><topic>Hepatitis B Core Antigens - genetics</topic><topic>Hepatitis B Core Antigens - immunology</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B Virus, Duck - genetics</topic><topic>Hepatitis B Virus, Duck - immunology</topic><topic>Hepatitis, Viral, Animal - immunology</topic><topic>Immune Tolerance</topic><topic>Lamivudine - therapeutic use</topic><topic>Liver - virology</topic><topic>Microbiology</topic><topic>Miscellaneous</topic><topic>Vaccines, DNA - genetics</topic><topic>Vaccines, DNA - immunology</topic><topic>Viral Envelope Proteins - genetics</topic><topic>Viral Envelope Proteins - immunology</topic><topic>Viremia</topic><topic>Virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thermet, Alexandre</creatorcontrib><creatorcontrib>Buronfosse, Thierry</creatorcontrib><creatorcontrib>Werle-Lapostolle, Bettina</creatorcontrib><creatorcontrib>Chevallier, Michele</creatorcontrib><creatorcontrib>Pradat, Pierre</creatorcontrib><creatorcontrib>Trepo, Christian</creatorcontrib><creatorcontrib>Zoulim, Fabien</creatorcontrib><creatorcontrib>Cova, Lucyna</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of general virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thermet, Alexandre</au><au>Buronfosse, Thierry</au><au>Werle-Lapostolle, Bettina</au><au>Chevallier, Michele</au><au>Pradat, Pierre</au><au>Trepo, Christian</au><au>Zoulim, Fabien</au><au>Cova, Lucyna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection</atitle><jtitle>Journal of general virology</jtitle><addtitle>J Gen Virol</addtitle><date>2008-05-01</date><risdate>2008</risdate><volume>89</volume><issue>5</issue><spage>1192</spage><epage>1201</epage><pages>1192-1201</pages><issn>0022-1317</issn><eissn>1465-2099</eissn><coden>JGVIAY</coden><abstract>1 INSERM, Unit 871, F-69424 Lyon, France
2 Université Lyon 1, IFR62, F-69008 Lyon, France
3 Ecole Nationale Vétérinaire de Lyon, F-69280 Marcy l'Etoile, France
4 Pathology Department, Marcel Mérieux Laboratory, F-69007 Lyon, France
5 Hospices Civiles de Lyon, Department of Hepatology, Hotel-Dieu, F-69002 Lyon, France
Correspondence Lucyna Cova cova{at}lyon.inserm.fr
This study used a duck hepatitis B virus (DHBV) model to evaluate whether a novel DNA vaccination protocol alone or associated with antiviral (lamivudine) treatment was able to clear the intrahepatic covalently closed, circular viral DNA (cccDNA) pool responsible for persistence of infection. DHBV carriers received DNA vaccine (on weeks 6, 10, 13, 14, 28 and 35) targeting the large envelope and/or core proteins alone or combined with lamivudine treatment (on weeks 1–8) or lamivudine monotherapy. After 10 months of follow-up, a dramatic decrease in viraemia and liver DHBV cccDNA (below 0.08 cccDNA copies per cell) was observed in 9/30 ducks (30 %) receiving DNA mono- or combination therapy, compared with 0/12 (0 %) from lamivudine monotherapy or the control groups, suggesting a significant antiviral effect of DNA immunization. However, association with the drug did not significantly improve DHBV DNA vaccine efficacy (33 % cccDNA clearance for the combination vs 27 % for DNA monotherapy), probably due to the low antiviral potency of lamivudine in the duck model. Seroconversion to anti-preS was observed in 6/9 (67 %) ducks showing cccDNA clearance, compared with 1/28 (3.6 %) without clearance, suggesting a significant correlation ( P <0.001) between humoral response restoration and cccDNA elimination. Importantly, an early (weeks 10–12) drop in viraemia was observed in seroconverted animals, and virus replication did not rebound following the cessation of immunotherapy, indicating a sustained effect. This study provides the first evidence that therapeutic DNA vaccination is able to enhance hepadnaviral cccDNA clearance, which is tightly associated with a break in humoral immune tolerance. These results also highlight the importance of antiviral drug potency and an effective DNA immunization protocol for the design of therapeutic vaccines against chronic hepatitis B.</abstract><cop>Reading</cop><pub>Soc General Microbiol</pub><pmid>18420797</pmid><doi>10.1099/vir.0.83583-0</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of general virology, 2008-05, Vol.89 (5), p.1192-1201 |
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| source | MEDLINE; Microbiology Society; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Biological and medical sciences DNA, Viral - genetics Duck hepatitis B virus Ducks Follow-Up Studies Fundamental and applied biological sciences. Psychology Hepadnaviridae Infections - immunology Hepatitis B Antibodies - blood Hepatitis B Core Antigens - genetics Hepatitis B Core Antigens - immunology Hepatitis B virus Hepatitis B Virus, Duck - genetics Hepatitis B Virus, Duck - immunology Hepatitis, Viral, Animal - immunology Immune Tolerance Lamivudine - therapeutic use Liver - virology Microbiology Miscellaneous Vaccines, DNA - genetics Vaccines, DNA - immunology Viral Envelope Proteins - genetics Viral Envelope Proteins - immunology Viremia Virology |
| title | DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection |
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