When viruses collide: hepatitis B virus reactivation after hepatitis C treatment
Ashwin Balagopal, Chloe L. Thio
Ashwin Balagopal, Chloe L. Thio
Published May 18, 2020
Citation Information: J Clin Invest. 2020;130(6):2823-2826. https://doi.org/10.1172/JCI137477.
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Commentary

When viruses collide: hepatitis B virus reactivation after hepatitis C treatment

Abstract

Treatment for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) in hepatitis B virus (HBV) coinfection can result in HBV reactivation. In this issue of the JCI, Cheng and colleagues explored the role of interferon signaling in the complex interaction between HBV and HCV using cell lines, mouse models, and samples from people with coinfection. Notably, HCV enhanced interferon signaling, as measured by interferon-stimulated gene (ISG) expression, and decreased HBV transcription and replication. Blockade of interferon signaling reversed the effects on HBV replication. Further, pharmacologic inhibition of HCV replication in vitro and in coinfected humanized mice also reduced interferon signaling and, correspondingly, increased HBV replication. Intriguingly, baseline serum levels of the ISG CXCL10 predicted HBV reactivation in a cohort of coinfected people taking DAAs. Determining how interferon signaling silences HBV transcription and whether serum CXCL10 predicts HBV reactivation in a clinical setting are questions that warrant further investigation.

Authors

Ashwin Balagopal, Chloe L. Thio

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Figure 1

Hepatitis B and C coinfection are intertwined by the type 1 interferon response.

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Hepatitis B and C coinfection are intertwined by the type 1 interferon r...
(A) In HBV monoinfection, virions infect hepatocytes and uncoat, yielding the relaxed circular DNA (rcDNA) that is converted to covalently closed circular DNA (cccDNA) by host nuclear polymerases. cccDNA is the template for transcription of pregenomic RNA (pgRNA) and other viral RNAs (not pictured). pgRNA is exported into the cytoplasm, encapsidated, and reverse transcribed by the HBV polymerase into rcDNAs that egress as infectious virions. HBV fails to trigger the innate immune type 1 interferon signaling cascade. (B) In HCV monoinfection, virions infect hepatocytes and uncoat. The single-stranded RNA template is translated into nonstructural proteins that replicate progeny RNA molecules in membranous webs. Encapsidated progeny RNAs egress as infectious virions. The viral genomes trigger intracellular innate immune sensors, leading to type 1 interferon production. Type 1 interferons ligate interferon α receptors (IFNAR1/2) on neighboring hepatocytes, triggering JAK/STAT signaling that terminates in transcription of hundreds of antiviral ISGs. (C) In HBV-HCV coinfection, HCV infection triggers type 1 interferon release that is sensed by HBV-infected hepatocytes. Upregulated ISG expression in HBV-infected hepatocytes associates with decreased abundance of HBV transcripts and decreased HBV replication. (D) DAAs that inhibit HCV replication are associated with dampening type 1 interferon responses. Similarly, JAK inhibitors (Jaki) block the signaling cascade following IFNAR1/2 ligation, inhibiting upregulation of ISG expression. Both DAAs and JAKi result in the derepression of HBV transcription and increased HBV replication. This also increases the number of cells that show coinfection with HBV and HCV.