Rnai-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis b virus DNA is a source of hbsag

Christine I. Wooddell, Man Fung Yuen, Henry Lik Yuen Chan, Robert G. Gish, Stephen A. Locarnini, Deborah Chavez, Carl Ferrari, Bruce D. Given, James Hamilton, Steven B. Kanner, Ching Lung Lai, Johnson Y.N. Lau, Thomas Schluep, Zhao Xu, Robert E. Lanford, David L. Lewis

    Research output: Contribution to journalArticlepeer-review

    173 Scopus citations

    Abstract

    Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)-based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received longterm therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

    Original languageEnglish (US)
    Article numbereaan0241
    JournalScience translational medicine
    Volume9
    Issue number409
    DOIs
    StatePublished - Sep 27 2017

    ASJC Scopus subject areas

    • Medicine(all)

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