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 2

Jaki or SOF treatment of mono- and coinfected PHHs.

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Jaki or SOF treatment of mono- and coinfected PHHs. (A) Schematic repres...
(A) Schematic representation of the experimental setting. PHHs (lot Hu1574) were infected with HBV or mock infected for 6 days and followed by HCV superinfection at MOI = 1 TCID50/cell for 3 days. One micromolar ETV, 5 μM Jaki, or 10 μM SOF was added to mono- or superinfected cells for 3 days before harvesting the cells for analysis. (B) Relative HBV and HCV levels and (C) ISG expression were measured by RT-qPCR. Relative viral levels were determined by normalizing to monoinfected nontreated samples set as 100 and are shown in linear scale. Relative ISG levels were determined by normalizing to HBV-monoinfected nontreated samples (set as 1) and are shown in log10 scale (CXCL10 and ISG15) or linear scale (A3G and ISG20). 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. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. NS, not significant. The results are representative of 3 separate experiments. Triplicate wells were used for each group.