Research ArticleInfectious Disease

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg

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Science Translational Medicine  27 Sep 2017:
Vol. 9, Issue 409, eaan0241
DOI: 10.1126/scitranslmed.aan0241

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How hepatitis hangs around

Hepatitis B virus (HBV) infects the liver, and chronic infection can lead to cirrhosis or cancer. Wooddell et al. report the results of a phase 2 trial of a drug based on RNA interference, which was unable to reduce viral burden in certain subsets of patients. To determine the mechanism of this variable response, the researchers examined chronically infected chimpanzees that had been treated with the drug. They found evidence that viral antigen was being produced from integrated HBV transcripts that did not harbor the target sequence. This study uncovers a previously unappreciated source of viral antigen, which could inform disease pathogenesis and help guide development of future HBV treatments.

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 long-term 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.

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