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Woodchuck hepatitis virus core gene deletions and proliferative responses of peripheral blood mononuclear cells stimulated by an immunodominant epitope: a viral immune escape in the woodchuck model of chronic hepatitis B?

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Abstract

Marmota monax and its natural infection by woodchuck hepatitis virus (WHV) could be used as a predictive model for evaluating mechanisms of viral persistence during chronic hepatitis B virus (HBV) infection. The aim of this study was to investigate the presence of viral variants in the core gene of chronically WHV-infected woodchucks that showed two different patterns of peripheral blood mononuclear cells’ (PBMCs’) responses after stimulation with a specific WHV core peptide. Sequences’ analysis of the WHV core region from eight WHV chronically infected woodchucks have been performed after in vitro stimulation with an immunodominant epitope of the WHV core protein (amino acids [aa] 96-110). Following this stimulation, positive PBMC responses at each point of follow-up were observed for four animals (group A), and weak immune responses at one or a few points of follow-up were observed for the remaining four animals (group B). The WHV core gene sequences contained amino acid deletions (aa 84-126, aa 84-113) in three of four group A animals and in none of group B animals. In the group A animals, the same deletions were observed in liver specimens and in two of four tumor specimens. Hepatocellular carcinoma (HCC) was diagnosed in all group A animals and in one group B animal. In conclusion, internal deletions in the core region correlated with a sustained PBMC response to the immunogenic peptide (96-110) of the core protein. A possible role of this relationship in hepatocarcinogenesis could be hypothesized; however, this needs to be investigated in patients with chronic HBV infection. The evaluation of virus-specific T-cell responses and T-cell epitopes that are possibly related to the mechanisms of viral evasion should be further investigated in order to design combined antiviral and immune approaches to control chronic HBV infection.

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Acknowledgments

We wish to acknowledge Prof. Carlo Ferrari for his critical revision of the manuscript. Gratitude is also expressed to the staff of the animal housing facility, to Andrea Sagrestani, to Andrea Giovannelli for technical assistance, and to Valter Tranquilli and Romina Tomasetto for editing support. This work was supported by MIUR Project 6254 on “HBV Therapeutic Vaccination: Application of Marmota monax Model” and by ISS/Ministry of Health Project no. 40 “Nuove strategie di immunoterapia per l’infezione cronica da HBV”.

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Authors and Affiliations

  1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Roberto Giuseppetti & Emilio D’Ugo

  2. Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Stefania Taffon, Anna Rita Ciccaglione, Barbara Pulimanti & Maria Rapicetta

  3. Center for Immunobiologicals Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Loreta A. Kondili

  4. Department of Clinical Medicine, Sapienza University of Rome, Viale dell’Università 37, 00161, Rome, Italy

    Loreta A. Kondili & Adolfo F. Attili

Authors
  1. Stefania Taffon
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  2. Loreta A. Kondili
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  3. Roberto Giuseppetti
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  4. Anna Rita Ciccaglione
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  5. Barbara Pulimanti
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  6. Adolfo F. Attili
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  7. Maria Rapicetta
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  8. Emilio D’Ugo
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Correspondence to Emilio D’Ugo.

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Taffon, S., Kondili, L.A., Giuseppetti, R. et al. Woodchuck hepatitis virus core gene deletions and proliferative responses of peripheral blood mononuclear cells stimulated by an immunodominant epitope: a viral immune escape in the woodchuck model of chronic hepatitis B?. Arch Virol 160, 1065–1073 (2015). https://doi.org/10.1007/s00705-015-2346-x

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  • DOI: https://doi.org/10.1007/s00705-015-2346-x

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