Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection
Xiaoming Cheng, … , Kazuaki Chayama, T. Jake Liang
Xiaoming Cheng, … , Kazuaki Chayama, T. Jake Liang
Published March 12, 2020
Citation Information: J Clin Invest. 2020;130(6):3205-3220. https://doi.org/10.1172/JCI135616.
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Research Article Hepatology Virology

Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection

Abstract

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV–coinfected persons.

Authors

Xiaoming Cheng, Takuro Uchida, Yuchen Xia, Regina Umarova, Chun-Jen Liu, Pei-Jer Chen, Anuj Gaggar, Vithika Suri, Marcus M. Mücke, Johannes Vermehren, Stefan Zeuzem, Yuji Teraoka, Mitsutaka Osawa, Hiroshi Aikata, Keiji Tsuji, Nami Mori, Shuhei Hige, Yoshiyasu Karino, Michio Imamura, Kazuaki Chayama, T. Jake Liang

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Figure 3

In situ RNA detection of viral replication and IFNL1 expression in mono- and coinfected PHHs.

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In situ RNA detection of viral replication and IFNL1 expression in mono-...
(A) Schematic representation of the experimental setting. PHHs (lot Hu1794) were first infected with HBV for 6 days, followed by HCV superinfection for 2 days in the presence of 5 μM Jaki as indicated. (B) Probe sets targeting HBV nucleic acids, HCV RNA, and IFNL1 mRNA were used to stain all the cells. Signals are shown as green for HBV, red for HCV, white for IFNL1, and blue for cell nuclei (counterstained by DAPI). Scale bars: 20 μm. (C) Virus-infected cells were defined as having signal dots higher in number than noninfected control cells. Infection efficiency for each virus was calculated as percentage of total number of cells counted in each condition. (D) Numbers of target dots in individual cells were plotted. Cells with 0 signal dots were input as 0.1. Four random views were analyzed. Details of image quantification can be found in Supplemental Methods. Unpaired t test was used for comparisons. Means ± SEM are shown. NS, not significant. **P < 0.01; ****P < 0.0001. The results are representative of 3 separate experiments.