Single hepatocytes show persistence and transcriptional inactivity of hepatitis B
- Johns Hopkins Univ., Baltimore, MD (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Lisbon (Portugal)
- Virginia Commonwealth Univ., Richmond, VA (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
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
Similar Records
Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes
Duck hepatitis B virus covalently closed circular DNA appears to survive hepatocyte mitosis in the growing liver