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

Journal Article · · JCI Insight
 [1]; ORCiD logo [1]; ORCiD logo [2];  [1];  [1]; ORCiD logo [1];  [1]; ORCiD logo [1];  [3];  [1]; ORCiD logo [4];  [1];  [1];  [1]
  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)
+ Show Author Affiliations

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.

Research Organization:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
89233218CNA000001; R01 AI138810; R01 AI116269; R01 AI116868; R01 OD011095; R01 DK094818; K24 DA034621
OSTI ID:
1825438
Report Number(s):
LA-UR-20-22940
Journal Information:
JCI Insight, Vol. 5, Issue 19; Conference: HEP DART 2019, Kauai, Hawaii (United States), 9 Dec 2019; ISSN 2379-3708
Publisher:
American Society for Clinical InvestigationCopyright Statement
Country of Publication:
United States
Language:
English

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