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Single hepatocytes show persistence and transcriptional inactivity of hepatitis B
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 pre...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566712/ https://www.ncbi.nlm.nih.gov/pubmed/33004689 http://dx.doi.org/10.1172/jci.insight.140584 |
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author | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy M. 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_facet | Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy M. 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_sort | Balagopal, Ashwin |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7566712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-75667122020-10-21 Single hepatocytes show persistence and transcriptional inactivity of hepatitis B Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy M. 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. JCI Insight Research Article 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. American Society for Clinical Investigation 2020-10-02 /pmc/articles/PMC7566712/ /pubmed/33004689 http://dx.doi.org/10.1172/jci.insight.140584 Text en © 2020 Balagopal et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Balagopal, Ashwin Grudda, Tanner Ribeiro, Ruy M. 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. Single hepatocytes show persistence and transcriptional inactivity of hepatitis B |
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 | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566712/ https://www.ncbi.nlm.nih.gov/pubmed/33004689 http://dx.doi.org/10.1172/jci.insight.140584 |
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