Publicação
Single hepatocytes show persistence and transcriptional inactivity of hepatitis B
| Resumo: | There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure. |
|---|---|
| Autores principais: | Balagopal, Ashwin |
| Outros Autores: | Grudda, Tanner; Ribeiro, Ruy; Saad, Yasmeen S.; Hwang, Hyon S.; Quinn, Jeffrey; Murphy, Michael; Ward, Kathleen; Sterling, Richard K.; Zhang, Yang; Perelson, Alan S.; Sulkowski, Mark S.; Osburn, William O.; Thio, Chloe L. |
| Assunto: | Hepatitis Hepatology Infectious disease Molecular biology |
| Ano: | 2020 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1866810329447530496 |
|---|---|
| author | Balagopal, Ashwin |
| author2 | Grudda, Tanner Ribeiro, Ruy Saad, Yasmeen S. Hwang, Hyon S. Quinn, Jeffrey Murphy, Michael Ward, Kathleen Sterling, Richard K. Zhang, Yang Perelson, Alan S. Sulkowski, Mark S. Osburn, William O. Thio, Chloe L. |
| author2_role | author author author author author author author author author author author author author |
| author_facet | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy Saad, Yasmeen S. Hwang, Hyon S. Quinn, Jeffrey Murphy, Michael Ward, Kathleen Sterling, Richard K. Zhang, Yang Perelson, Alan S. Sulkowski, Mark S. Osburn, William O. Thio, Chloe L. |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Balagopal, Ashwin\"},{\"Person.name\":\"Grudda, Tanner\"},{\"Person.name\":\"Ribeiro, Ruy\",\"Person.identifier.orcid\":\"0000-0002-3988-8241\"},{\"Person.name\":\"Saad, Yasmeen S.\"},{\"Person.name\":\"Hwang, Hyon S.\"},{\"Person.name\":\"Quinn, Jeffrey\"},{\"Person.name\":\"Murphy, Michael\"},{\"Person.name\":\"Ward, Kathleen\"},{\"Person.name\":\"Sterling, Richard K.\"},{\"Person.name\":\"Zhang, Yang\"},{\"Person.name\":\"Perelson, Alan S.\"},{\"Person.name\":\"Sulkowski, Mark S.\"},{\"Person.name\":\"Osburn, William O.\"},{\"Person.name\":\"Thio, Chloe L.\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy Saad, Yasmeen S. Hwang, Hyon S. Quinn, Jeffrey Murphy, Michael Ward, Kathleen Sterling, Richard K. Zhang, Yang Perelson, Alan S. Sulkowski, Mark S. Osburn, William O. Thio, Chloe L. |
| datacite.date.Accepted.fl_str_mv | 2020-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2020-12-02T13:16:28Z |
| datacite.date.embargoed.fl_str_mv | 2020-12-02T13:16:28Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Hepatitis Hepatology Infectious disease Molecular biology |
| datacite.titles.title.fl_str_mv | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy Saad, Yasmeen S. Hwang, Hyon S. Quinn, Jeffrey Murphy, Michael Ward, Kathleen Sterling, Richard K. Zhang, Yang Perelson, Alan S. Sulkowski, Mark S. Osburn, William O. Thio, Chloe L. |
| dc.date.Accepted.fl_str_mv | 2020-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2020-12-02T13:16:28Z |
| dc.date.embargoed.fl_str_mv | 2020-12-02T13:16:28Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/45062 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | American Society for Clinical Investigation |
| dc.rights.cclincense.fl_str_mv | http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Hepatitis Hepatology Infectious disease Molecular biology |
| dc.title.fl_str_mv | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/8adc2692-aad6-444a-a828-457db6080464/download |
| id | ul_915fdcbfd2a2a4e57041d8f79e8ce1e9 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/45062 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/45062 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy Ribeiro, Ruy https://www.ciencia-id.pt/9A15-E40B-738F 9A15-E40B-738F http://orcid.org/0000-0002-3988-8241 0000-0002-3988-8241 Saad, Yasmeen S. Hwang, Hyon S. Quinn, Jeffrey Murphy, Michael Ward, Kathleen Sterling, Richard K. Zhang, Yang Perelson, Alan S. Sulkowski, Mark S. Osburn, William O. Thio, Chloe L. |
| publishDate | 2020 |
| publisher.none.fl_str_mv | American Society for Clinical Investigation |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engAmerican Society for Clinical Investigationpt_PTThere is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure.application/pdfpt_PTSingle hepatocytes show persistence and transcriptional inactivity of hepatitis BBalagopal, AshwinGrudda, TannerPersonalRibeiro, RuyDSpacehttp://dspace.org/items/215b5cf4-faab-41ea-becf-c63bed56d3d1DSpacehttp://dspace.org/items/215b5cf4-faab-41ea-becf-c63bed56d3d1RibeiroRuy MiguelCiência IDhttps://www.ciencia-id.pt9A15-E40B-738FORCIDhttp://orcid.org0000-0002-3988-8241Saad, Yasmeen S.Hwang, Hyon S.Quinn, JeffreyMurphy, MichaelWard, KathleenSterling, Richard K.Zhang, YangPerelson, Alan S.Sulkowski, Mark S.Osburn, William O.Thio, Chloe L.HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptDOIIsPartOf10.1172/jci.insight.1405842020-12-02T13:16:28Z20202020-01-01T00:00:00ZHandlehttp://hdl.handle.net/10451/45062http://purl.org/coar/access_right/c_abf2open accessHepatitisHepatologyInfectious diseaseMolecular biology4078158 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal article2020http://creativecommons.org/licenses/by/4.0/http://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/8adc2692-aad6-444a-a828-457db6080464/downloadJCI Insight519 |
| spellingShingle | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B Balagopal, Ashwin Hepatitis Hepatology Infectious disease Molecular biology |
| status | SINGLETON |
| subject.fl_str_mv | Hepatitis Hepatology Infectious disease Molecular biology |
| title | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| title_full | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| title_fullStr | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| title_full_unstemmed | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| title_short | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| title_sort | Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
| topic | Hepatitis Hepatology Infectious disease Molecular biology |
| topic_facet | Hepatitis Hepatology Infectious disease Molecular biology |
| url | http://hdl.handle.net/10451/45062 |
| visible | 1 |