Different antiviral effects of IFNα and IFNβ in an HBV mouse model

Zhou, Yun; Li, Sheng; Tang, Zhe; Xu, Chunli; Huang, Shunmei; Wu, Jun; Dittmer, Ulf; Dickow, Julia; Sutter, Kathrin; Lu, Mengji; Yang, Dongliang; Song, Jinzhu

doi:10.1016/j.imbio.2016.11.003

Cited by 10 publications

(9 citation statements)

References 52 publications

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“…However, whether IFN‐α could induce IL‐6 expression in hepatocytes is still unknown. In fact, it has been reported that IFN‐α resulted in elevated expression levels of IL‐6 in the liver of HBV mouse model . Here, our study first demonstrated the ability of IFN‐α to directly induce IL‐6 secretion from hepatocytes.…”

Section: Discussionsupporting

confidence: 52%

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Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Yang

Guan

Zhang

et al. 2019

Journal of Medical Virology

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Interleukin 6 (IL‐6) is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells, including hepatocytes. Previous studies have shown that serum IL‐6 levels are increased in hepatitis B patients. However, the role of IL‐6 in modulating the anti‐hepatitis B virus (HBV) activity of interferon‐α (IFN‐α) remains unclear. In this study, we found that both HBV and viral proteins could induce the expression of IL‐6 in hepatocytes (LO2 and HepG2). Exogenous IL‐6 had no effect on HBV replication, whereas knockdown of IL‐6 expression by RNAi inhibited that. Interestingly, IFN‐α markedly induced IL‐6 expression in hepatocytes, especially in HBV replicating hepatocytes. In turn, IL‐6 impaired the anti‐HBV efficiency of IFN‐α by decreases the expression of IFN‐α downstream effectors by upregulation of suppressor of cytokine signaling‐3 (SOCS3). Furthermore, we demonstrated that downregulation of SOCS3 improved IFN antiviral activity to some extent in HBV replicating hepatocytes. These data provided new insights for a better understanding of the mechanism of IFN‐α resistance and may represent a novel therapeutic strategy to efficiently target HBV infection.

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Section: Discussionsupporting

confidence: 52%

“…In fact, it has been reported that IFN-α resulted in elevated expression levels of IL-6 in the liver of HBV mouse model. 39,40 Here, our study first demonstrated the ability of IFN-α to directly induce IL-6 secretion from hepatocytes. Notably, in HBVinfected hepatocytes, stimulation with IFN-α also potently induced IL-6 expression.…”

Section: Discussionmentioning

confidence: 78%

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Yang

Guan

Zhang

et al. 2019

Journal of Medical Virology

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“…the host immune response to both HCV and HBV may be attenuated by the eradication of HCV and thereby cause HBV reactivation. [ 22 , 23 ]…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus reactivation after successful treatment of hepatitis C virus with sofosbuvir and ribavirin

Miyasaka¹,

Yoshida²,

Suzuki³

et al. 2020

Medicine

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Rationale: Hepatitis B virus (HBV) reactivation caused by immunosuppressive therapy or chemotherapy is well known. The administration of direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has also been reported to cause HBV reactivation. We report a rare case of HBV reactivation in a patient with HCV infection after DAA therapy. Patient concerns: In 1996, a 53-year-old female was identified as infected with HCV at a medical check-up, following which she visited our hospital. She was infected with HCV genotype 2b, and at follow up in 1997, was found to be hepatitis B surface antigen (HBsAg) and antibody against HBsAg negative, antibody against HBV core positive. She then experienced malignant lymphoma in 2001 at 58 years of age. Complete remission was achieved following chemotherapy and autologous peripheral blood stem cell transplantation. In 2014, she remained negative for HBsAg and antibody against HBsAg but positive for antibody against HBV core. In 2015, 12 weeks of sofosbuvir and ribavirin treatment for HCV was started. Serum HCV RNA levels rapidly decreased, and HCV elimination was confirmed at 24 weeks after cessation of DAA treatment. Acute hepatitis B developed at 15 weeks post- sustained virological response without any symptoms and physical examination findings. Diagnoses: This case is speculated to represent HBV reactivation induced by DAA treatment in a patient with previously resolved HBV, based on virologic and clinical status. Genome sequencing revealed the HBV genotype as A2. Interventions: The patient was treated with nucleotide analog for HBV reactivation once a day. Outcomes: Serum HBV-DNA levels decreased, and serum liver enzymes improved following initiation of nucleotide analog treatment. Also, adverse events of nucleotide analog treatment were not observed. Lessons: Although the risk may be very low, DAA therapy can cause HBV reactivation in chronic hepatitis C patients with prior HBV infection. Thus, those patients must be closely monitored for serum HBV DNA levels during and after DAA treatment.

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“…21 For example, a recent study reported that IFN-free DAA-based therapy reduced the expression of hepatic IFN-stimulated genes (ISGs) and type III IFN genes in patients with hepatitis C. 22 The levels of hepatic ISGs were found to be correlated with HBV clearance after the application of IFNα and IFNβ in an HBV hydrodynamic injection mouse model. 23 Supernatant containing IFN-λ 3, one of the type III IFNs, which was derived from adefovir-treated colon cancer cells, induced ISGs and suppressed the production of HBsAg in hepatoma cell lines. 24 Thus, the host immune response(s) to both HCV and HBV may be attenuated by the eradication of HCV and thereby cause HBV reactivation.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous remission of hepatitis B virus reactivation during direct‐acting antiviral agent‐based therapy for chronic hepatitis C

Sato

Kobayashi

Yamazaki

et al. 2017

Hepatology Research

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The administration of direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has been reported to cause hepatitis B virus (HBV) reactivation. However, the actual conditions of HBV reactivation and the ideal timing of medical intervention have not been fully evaluated. We report the cases of two female patients dually infected with HBV and HCV. Both patients were inactive HBV carriers. Although the serum HCV RNA levels promptly decreased after the initiation of DAA-based therapy, the serum HBV DNA levels gradually increased during DAA-based therapy, with the peak serum HBV DNA levels observed at 16 weeks after the initiation of DAA-based therapy in both cases. Subsequently, we checked the serum HBV DNA levels closely every week several times. Fortunately, the serum HBV DNA levels gradually decreased without medical intervention. Neither case developed an alanine aminotransferase flare-up. The HCV genotypes were 2a and 1b, and the DAA-based therapies of Cases 1 and 2 were 12 weeks of sofosbuvir/ribavirin and ombitasvir/paritaprevir/ritonavir, respectively. The significance of our case reports is the demonstration of the existence of spontaneous remission of HBV reactivation that developed during DAA-based therapy, the avoidance of intervention of nucleot(s)ide analogs by frequent monitoring of serum HBV DNA levels, and development of HBV reactivation regardless of the viral genotype or class of DAA. In conclusion, the close monitoring of serum HBV DNA levels during and after DAA-based therapy is essential and medical intervention for HBV reactivation should be carefully considered on an individual basis.

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Different antiviral effects of IFNα and IFNβ in an HBV mouse model

Cited by 10 publications

References 52 publications

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Hepatitis B virus reactivation after successful treatment of hepatitis C virus with sofosbuvir and ribavirin

Spontaneous remission of hepatitis B virus reactivation during direct‐acting antiviral agent‐based therapy for chronic hepatitis C

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