Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis

Xia, Yuchen; Stadler, Daniela; Lucifora, Julie; Reisinger, Florian; Webb, Dennis; Hösel, Marianna; Michler, Thomas; Wisskirchen, Karin; Cheng, Xiaoming; Zhang, Ke; Chou, Wen-Min; Wettengel, Jochen M.; Malo, Antje; Bohne, Felix; Hoffmann, Dieter; Eyer, Florian; Thimme, Robert; Falk, Christine S.; Thasler, Wolfgang E.; Heikenwälder, Mathias

doi:10.1053/j.gastro.2015.09.026

Cited by 259 publications

(299 citation statements)

References 38 publications

(61 reference statements)

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“…Longitudinal immunological analyses revealed that NK cells are activated and produce IFN-c prior to the increase in HBV antigen-specific CD4 or CD8 T cells [10]. IFN-c, TNF-a, and IFN-a have been reported to be key players in the mediation of non-cytopathic HBV eradication [5,[11][12][13]. Of interest are the findings that IFN-c and TNF-a were able to induce APOBEC3 deaminase, resulting in the reduction of cccDNA in hepatocytes [5,13].…”

Section: Innate Immunity In Hbv Infection: the Role Of Nk Cells And Dcsmentioning

confidence: 99%

“…IFN-c, TNF-a, and IFN-a have been reported to be key players in the mediation of non-cytopathic HBV eradication [5,[11][12][13]. Of interest are the findings that IFN-c and TNF-a were able to induce APOBEC3 deaminase, resulting in the reduction of cccDNA in hepatocytes [5,13]. These data suggest that NK cells could play important roles in non-cytopathic HBV clearance before adaptive immune responses are fully evoked.…”

Section: Innate Immunity In Hbv Infection: the Role Of Nk Cells And Dcsmentioning

confidence: 99%

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Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Section: Innate Immunity In Hbv Infection: the Role Of Nk Cells And Dcsmentioning

confidence: 99%

Section: Innate Immunity In Hbv Infection: the Role Of Nk Cells And Dcsmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…APOBEC3 can deaminate doublestranded DNA cytidines to uridines [71] and induce cccDNA degradation. IFNγ and TNFα produced form Tcells can induce deamination of cccDNA without cytolysis, supporting the essential role of APOBEC3 in reduction of cccDNA [53] . Collectively, type1 IFNmediated effects, especially APOBEC3 upregulation, will be a key subject for development of new therapeutics.…”

Section: Impairment Of Innate Immune Responsementioning

confidence: 74%

“…Because HBV transgenic mice do not have cccDNA [52] , the effects of these cytokines on cccDNA were unclear. In cccDNAexpressing cultured cells, however, IFNγ and TNFα inhibited HBV replication and reduced cccDNA in an additive manner [53] . Moreover, the decay of cccDNA was found to require activation of APOBEC3 deaminases [53] , which are expressed in liver tissues of individuals with acute, but not chronic, HBV infection.…”

Section: Acute Infectionmentioning

confidence: 99%

“…In cccDNAexpressing cultured cells, however, IFNγ and TNFα inhibited HBV replication and reduced cccDNA in an additive manner [53] . Moreover, the decay of cccDNA was found to require activation of APOBEC3 deaminases [53] , which are expressed in liver tissues of individuals with acute, but not chronic, HBV infection. These observations indicate that HBVspecific Tcell activation followed by treatment with antiviral cytokines, such as IFNγ and TNFα, could eradicate HBV without cytolysis.…”

Section: Acute Infectionmentioning

confidence: 99%

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New horizon for radical cure of chronic hepatitis B virus infection

Tajiri¹,

Shimizu²

2016

WJH

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About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalentlyclosed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

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A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

Jiang,

Chen,

et al. 2024

Advanced Science

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Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody‐based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual‐domain‐engineered anti‐hepatitis B virus (HBV) therapeutic antibody 73‐DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV‐tolerant mice, administration of a single dose of 73‐DY at 2 mg kg−1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL−1 and suppress HBsAg to < 100 IU mL−1 for two weeks, demonstrating a dose‐lowering advantage of at least tenfold. Furthermore, 10 mg kg−1 of 73‐DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73‐DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long‐term immunotherapy with reverse chimeric 73‐DY facilitated the restoration of anti‐HBV immune responses. This study provides a foundation for the development of next‐generation antibody‐based CHB therapies.

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Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis

Abstract: IFNγ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay.

Cited by 259 publications

References 38 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

New horizon for radical cure of chronic hepatitis B virus infection

A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

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