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.
View: Text | PDF
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

×

Figure 5

Analysis of HBV-HCV coinfection in cDNA-uPA/SCID mice.

Options: View larger image (or click on image) Download as PowerPoint
Analysis of HBV-HCV coinfection in cDNA-uPA/SCID mice. (A) Thirty mice w...
(A) Thirty mice were infected with HBV for 4 weeks before 17 mice were randomly selected for HCV inoculation. All mice were maintained until week 10 after HBV inoculation, as shown by the schematic representation. (B) Serum HBV genome (upper) and human albumin (lower) concentrations were determined at the indicated time. (C) In a separate experiment, 9 mice were engrafted with PHHs from the same donor. Three of them were not infected and served as no-infection controls. Six were infected with HBV and on week 6 after HBV infection, 3 mice were coinfected with HCV until week 10. (D) Normalized hepatic HCV levels are presented as relative levels. Negative HCV RNA was input as 0. Normalized human IFNL1, CXCL10, and ISG20 levels relative to those of no-infection control (set as 1) are shown as fold induction. Details of RT-qPCR can be found in Supplemental Methods. Unpaired t test was used alone (D) or followed by Hochberg’s procedure to correct for multiple comparisons (B). Means ± SD are shown. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.