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Single hepatocytes show persistence and transcriptional inactivity of hepatitis B
Ashwin Balagopal 1 , Tanner Grudda 1 , Ruy M Ribeiro 2 3 , Yasmeen S Saad 1 , Hyon S Hwang 1 , Jeffrey Quinn 1 , Michael Murphy 1 , Kathleen Ward 1 , Richard K Sterling 4 , Yang Zhang 5 , Alan S Perelson 2 , Mark S Sulkowski 1 , William O Osburn 1 , Chloe L Thio 1
Affiliations
Affiliations
1
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
3
Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal.
4
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA.
5
Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA.
PMID: 33004689 DOI: 10.1172/jci.insight.140584
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 in all hepatocytes, resulting in a functional cure.
Keywords: Hepatitis; Hepatology; Infectious disease; Molecular biology; Transcription.
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