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 1

Kinetics of viral replication and host IFN responses in mono- and coinfected PHHs.

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Kinetics of viral replication and host IFN responses in mono- and coinfe...
(A) Schematic representation of the experimental setting. PHHs (lot Hu1832) were either monoinfected with HBV for 12 days or superinfected with HCV for 7 days starting on day 5 after HBV infection. (B) HBV replication was analyzed by qPCR for extracellular HBV-DNA, ELISA for HBsAg and HBeAg, and RT-qPCR for intracellular HBV-RNA. (C) HCV replication was measured by RT-qPCR for intracellular and extracellular HCV RNA and concurrent host cell IFN response was measured by RT-qPCR for (D) expression of IFNB and IFNL1, and (E) expression of ISG15, CXCL10, A3G, and ISG20. Time of sample collection is indicated on the x axis. Antigen measurements by ELISA were compared to background level from noninfected cell culture medium. Normalized gene expression relative to that of the HBV-monoinfected cells on 1 day post HCV infection (dp-C) (set as 1) are shown as relative levels for IFNB, IFNL1, ISG15, A3G, and ISG20. For CXCL10, the detection limit was set as 1. Details of RT-qPCR can be found in Supplemental Methods. Means ± SD are shown. Unpaired t test was followed by Hochberg’s procedure to correct for multiple comparisons (B). *P < 0.05; **P < 0.01; ***P < 0.001. The results are representative of 3 separate experiments. Triplicate wells were used for each group.