Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-Titer Hepatitis B Virus Carrier Mice

Michler, Thomas; Kosinska, Anna D.; Festag, Julia; Bunse, Till; Su, Jie; Ringelhan, Marc; Imhof, Hortenzia; Grimm, Dirk; Steiger, Katja; Mogler, Carolin; Heikenwälder, Mathias; Michel, M.-L.; Guzmán, Carlos A.; Milstein, Stuart; Sepp‐Lorenzino, Laura; Knolle, Percy; Protzer, Ulrike

doi:10.1053/j.gastro.2020.01.032

Cited by 90 publications

(107 citation statements)

References 34 publications

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“…HBVtg mice have been reported to develop HCC that show similar chromosomal aberrations and gene expression patterns to human HBV-associated HCC 53 . To study the effect of HBV on HIF transcriptional activity in this model system, HBVtg mice were treated with lipid nanoparticle complexed, liver-targeted siRNAs designed to silence all HBV transcripts (siHBV) 54 or with an unspecific control siRNA (siCtrl). The HBV-specific siRNA led to effective HBV silencing with greater than 95% reduction in HBeAg in the serum (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Liu

Harris

Marchi

et al. 2020

Sci Rep

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Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.

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Section: Resultsmentioning

confidence: 99%

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Liu

Harris

Marchi

et al. 2020

Sci Rep

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“…In mice with high antigen levels both HBsAg/MVA-S and HBcAg/MVA-core immunization failed to induce envelope and core-specific CD8 T cell responses in the spleen and in the liver, while vaccination in mice with low or intermediate antigen levels allowed expansion of anti-viral T cell responses and control of infection (75). Interestingly, HBV-specific CD8 T-cells were induced efficiently by therapeutic vaccination after RNAi-mediated suppression of hepatic antigen expression in highly antigenemic mice which were non-responsive to antigen stimulation before anti-viral therapy (76). Although very promising, translation of this therapeutic approach to the human natural infection may be not so easy because antigenemia in chronic patients is generally much higher and of longer duration than in this mouse model and because exposure to high antigen loads is only one of the multiple mechanisms of T cell inhibition which are simultaneously in place after decades of infection in chronic hepatitis patients.…”

Section: Persistent T Cell Exposure To High Viral Antigen Concentrationsmentioning

confidence: 99%

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

et al. 2020

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“…Livers were collected and analyzed 5 d after Cor93 T N transfer. subsequent therapeutic vaccination (Cobleigh et al, 2013;Michler et al, 2020).…”

Section: Spontaneous Hbsag Loss In Hbv Tg Mice Is Due To Hbsabmentioning

confidence: 99%

Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection

Fumagalli

Lucia

Venzin

et al. 2020

Journal of Experimental Medicine

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Antibody-mediated clearance of hepatitis B surface antigen (HBsAg) from the circulation of chronically infected patients (i.e., seroconversion) is usually associated with increased HBV-specific T cell responsiveness. However, a causative link between serum HBsAg levels and impairment of intrahepatic CD8+ T cells has not been established. Here we addressed this issue by using HBV replication-competent transgenic mice that are depleted of circulating HBsAg, via either spontaneous seroconversion or therapeutic monoclonal antibodies, as recipients of HBV-specific CD8+ T cells. Surprisingly, we found that serum HBsAg clearance has only a minimal effect on the expansion of HBV-specific naive CD8+ T cells undergoing intrahepatic priming. It does not alter their propensity to become dysfunctional, nor does it enhance the capacity of IL-2–based immunotherapeutic strategies to increase their antiviral function. In summary, our results reveal that circulating HBsAg clearance does not improve HBV-specific CD8+ T cell responses in vivo and may have important implications for the treatment of chronic HBV infection.

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Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-Titer Hepatitis B Virus Carrier Mice

Cited by 90 publications

References 34 publications

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection

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