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Title: Single hepatocytes show persistence and transcriptional inactivity of hepatitis B

Abstract

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 inmore » all hepatocytes, resulting in a functional cure.« less

Authors:
 [1]; ORCiD logo [1]; ORCiD logo [2];  [1];  [1]; ORCiD logo [1];  [1]; ORCiD logo [1];  [3];  [1]; ORCiD logo [4];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Johns Hopkins Univ., Baltimore, MD (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Lisbon (Portugal)
  3. Virginia Commonwealth Univ., Richmond, VA (United States)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1825438
Report Number(s):
LA-UR-20-22940
Journal ID: ISSN 2379-3708
Grant/Contract Number:  
89233218CNA000001; R01 AI138810; R01 AI116269; R01 AI116868; R01 OD011095; R01 DK094818; K24 DA034621
Resource Type:
Accepted Manuscript
Journal Name:
JCI Insight
Additional Journal Information:
Journal Volume: 5; Journal Issue: 19; Conference: HEP DART 2019, Kauai, Hawaii (United States), 9 Dec 2019; Journal ID: ISSN 2379-3708
Publisher:
American Society for Clinical Investigation
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Hepatology; Infectious disease

Citation Formats

Balagopal, Ashwin, Grudda, Tanner, Ribeiro, Ruy Miguel, 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., and Thio, Chloe L. Single hepatocytes show persistence and transcriptional inactivity of hepatitis B. United States: N. p., 2020. Web. doi:10.1172/jci.insight.140584.
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Balagopal, Ashwin, Grudda, Tanner, Ribeiro, Ruy Miguel, 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. United States. https://doi.org/10.1172/jci.insight.140584
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Balagopal, Ashwin, Grudda, Tanner, Ribeiro, Ruy Miguel, 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., and Thio, Chloe L. Fri . "Single hepatocytes show persistence and transcriptional inactivity of hepatitis B". United States. https://doi.org/10.1172/jci.insight.140584. https://www.osti.gov/servlets/purl/1825438.
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@article{osti_1825438,
title = {Single hepatocytes show persistence and transcriptional inactivity of hepatitis B},
author = {Balagopal, Ashwin and Grudda, Tanner and Ribeiro, Ruy Miguel and Saad, Yasmeen S. and Hwang, Hyon S. and Quinn, Jeffrey and Murphy, Michael and Ward, Kathleen and Sterling, Richard K. and Zhang, Yang and Perelson, Alan S. and Sulkowski, Mark S. and Osburn, William O. and Thio, Chloe L.},
abstractNote = {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.},
doi = {10.1172/jci.insight.140584},
journal = {JCI Insight},
number = 19,
volume = 5,
place = {United States},
year = {Fri Oct 02 00:00:00 EDT 2020},
month = {Fri Oct 02 00:00:00 EDT 2020}
}
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https://doi.org/10.1172/jci.insight.140584
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