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Kinetics of WHV-HDV replication in acute fatal course of woodchuck hepatitis

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Abstract

The objective of this study was to evaluate, by developing one-step real-time PCR, the outcome of superinfection with hepatitis D virus (HDV) genotype I in woodchucks that were chronic carriers of woodchuck hepatitis virus (WHV) and did not show relevant signs of liver damage. Three woodchucks (Marmota monax) chronically infected with WHV were superinfected with a woodchuck HDV inoculum. The evolution of the WHV and HDV infections was monitored by quantifying HDV-RNA, WHV-DNA, and HDV-WHV antigens and antibodies. WHV and HDV sequencing was also performed and liver markers were evaluated. Liver damage was assessed using the Ishak method. All woodchucks showed a high HDV viral load, antigenemia and short survival after superinfection. Histopathological examination of autoptic liver samples showed massive liver necrosis compatible with an acute fatal course of hepatitis. The WHV sequencing showed that the virus population was not substituted by the WHV inoculum. The HDV sequencing performed during superinfection and at autopsy indicated amino acid changes in immune dominant regions of the HDV antigen. The strong correlation between acute infection with HDV genotype I and rapid and fatal liver failure indicates that HDV can be an important factor in the prognosis of HDV-WHV-superinfected woodchucks.

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References

  1. Argentini C, La Sorsa V, Bruni R, D’Ugo E, Giuseppetti R, Rapicetta M (1999) Hepadnavirus evolution and molecular strategy of adaptation in a new host. J Gen Virol 80:617–626

    PubMed  CAS  Google Scholar 

  2. Bergmann KF, Cote PJ, Moriarty A, Gerin JL (1989) Hepatitis delta antigen: antigenic structure and humoral immune response. J Immunol 143:3714–3721

    PubMed  CAS  Google Scholar 

  3. Bonino F, Brunetto MR, Negro F, Smedile A, Ponzetto A (1991) Hepatitis delta virus, a model of liver cell pathology. J Hepatol 13:260–266

    Article  PubMed  CAS  Google Scholar 

  4. Casey JL, Gerin JL (2006) The woodchuck model of HDV infection. Curr Top Microbiol Immunol 307:211–225

    Article  PubMed  CAS  Google Scholar 

  5. Casey JL, Tennant BC, Gerin JL (2006) Genetic changes in hepatitis delta virus from acutely and chronically infected woodchucks. J Virol 80:6469–6477

    Article  PubMed  CAS  Google Scholar 

  6. Ciccaglione AR, Rapicetta M, Fabiano A, Argentini C, Silvestro M, Giuseppetti R, Varano F, D’Urso N, Dinolfo L, Morgando A, Bruni R, Ponzetto A (1993) Chronic infection in woodchucks infected by a cloned hepatitis delta virus. Arch Virol Suppl 8:15–21

    PubMed  CAS  Google Scholar 

  7. Colombo P, Di Blasi F, Magrin S, Fabiano C, Di Marco V, D’Amelio L, Lojacono F, Spinelli G, Craxì A (1991) Smouldering hepatitis B virus replication in patients with chronic liver disease and hepatitis delta virus superinfection. J Hepatol 12:64–69

    Article  PubMed  CAS  Google Scholar 

  8. Cote PJ, Toshkov I, Bellezza C, Ascenzi M, Roneker C, Ann Graham L, Baldwin BH, Gaye K, Nakamura I, Korba BE, Tennant BC, Gerin JL (2000) Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection. Hepatology 32:807–817

    Article  PubMed  CAS  Google Scholar 

  9. D’Ugo E, Kondili L, Canitano A, Catone S, Giuseppetti R, Gallinella B, Palmieri G, Orobello S, Argentini C, Glück R, Rapicetta M (2007) Rapid emergence of a viral resistant mutant in WHV chronically infected woodchucks treated with lamivudine and a pre-S/S CHO-derived hepatitis B virus vaccine. Vaccine 25:4895–4902

    Article  PubMed  CAS  Google Scholar 

  10. D’Ugo E, Paroli M, Palmieri G, Giuseppetti R, Argentini C, Tritarelli E, Bruni R, Barnaba V, Houghton M, Rapicetta M (2004) Immunization of woodchucks with adjuvanted sHDAg (p24): immune response and outcome following challenge. Vaccine 22:457–466

    Article  PubMed  CAS  Google Scholar 

  11. Farci P (2003) Delta hepatitis: an update. J Hepatol 39:S212–S219

    Article  PubMed  CAS  Google Scholar 

  12. Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, Schalm SW (2000) Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B: the European concerted action on viral hepatitis (Eurohep). Gut 46:420–426

    Article  PubMed  CAS  Google Scholar 

  13. Fiedler M, Roggendorf M (2006) Immunology of HDV infection. Curr Top Microbiol Immunol 307:187–209

    Article  PubMed  CAS  Google Scholar 

  14. Guilhot S, Huang SN, Xia YP, La Monica N, Lai MM, Chisari FV (1994) Expression of the hepatitis delta virus large and small antigens in transgenic mice. J Virol 68:1052–1058

    PubMed  CAS  Google Scholar 

  15. Hadziyannis SJ, Sherman M, Lieberman HM, Shafritz DA (1985) Liver disease activity and hepatitis B virus replication in chronic delta antigen–positive hepatitis B virus carriers. Hepatology 5:544–547

    Article  PubMed  CAS  Google Scholar 

  16. Huang YH, Tao MH, Hu CP, Syu WJ, Wu JC (2004) Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus. J Gen Virol 85:3089–3098

    Article  PubMed  CAS  Google Scholar 

  17. Huang YH, Wu JC, Hsu SC, Syu WJ (2003) Varied immunity generated in mice by DNA vaccines with large and small hepatitis delta antigens. J Virol 77:12980–12985

    Article  PubMed  CAS  Google Scholar 

  18. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN, Phillips MJ, Portmann BG, Poulsen H, Scheuer PJ, Schmid M, Thaler H (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22:696–699

    Article  PubMed  CAS  Google Scholar 

  19. Karayiannis P, Saldanha J, Jackson AM, Luther S, Goldin R, Monjardino J, Thomas HC (1993) Partial control of hepatitis delta virus superinfection by immunisation of woodchucks (Marmota monax) with hepatitis delta antigen expressed by a recombinant vaccinia or baculovirus. J Med Virol 41:210–214

    Article  PubMed  CAS  Google Scholar 

  20. Krogsgaard K, Kryger P, Aldershvile J, Andersson P, Sorensen TI, Nielsen JO (1987) Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 7:42–45

    Article  PubMed  CAS  Google Scholar 

  21. Lozano JL, Crespo J, de la Cruz F, Casafont F, Lopez-Arias MJ, Martín-Ramos L, Pons-Romero F (1994) Correlation between hepatitis B viremia and the clinical and histological activity of chronic delta hepatitis. Med Microbiol Immunol 183:159–167

    Article  PubMed  CAS  Google Scholar 

  22. Modahl LE, Lai MM (2000) Hepatitis delta virus: the molecular basis of laboratory diagnosis. Crit Rev Clin Lab Sci 37:45–92

    Article  PubMed  CAS  Google Scholar 

  23. Nakamura I, Nupp JT, Cowlen M, Hall WC, Tennant BC, Casey JL, Gerin JL, Cote PJ (2001) Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor-alpha messenger RNAs. Hepatology 33:439–447

    Article  PubMed  CAS  Google Scholar 

  24. Negro F, Korba BE, Forzani B, Baroudy BM, Brown TL, Gerin JL, Ponzetto A (1989) Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J Virol 63:1612–1618

    PubMed  CAS  Google Scholar 

  25. Nielsen M, Lundegaard C, Worning P, Lauemøller SL, Lamberth K, Buus S, Brunak S, Lund O (2003) Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci 12:1007–1017

    Article  PubMed  CAS  Google Scholar 

  26. Nisini R, Paroli M, Accapezzato D, Bonino F, Rosina F, Santantonio T, Sallusto F, Amoroso A, Houghton M, Barnaba V (1997) Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J Virol 71:2241–2251

    PubMed  CAS  Google Scholar 

  27. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring, Harbor

    Google Scholar 

  28. Saracco G, Rosina F, Brunetto MR, Amoroso P, Caredda F, Farci P, Piantino P, Bonino F, Rizzetto M (1987) Rapidly progressive HBsAg-positive hepatitis in Italy: the role of hepatitis delta virus infection. J Hepatol 5:274–281

    Article  PubMed  CAS  Google Scholar 

  29. Schlipköter U, Ponzetto A, Fuchs K, Rasshofer R, Choi SS, Roos S, Rapicetta M, Roggendorf M (1990) Different outcomes of chronic hepatitis delta virus infection in woodchucks. Liver 10:291–301

    PubMed  Google Scholar 

  30. Smedile A, Rosina F, Saracco G, Chiaberge E, Lattore V, Fabiano A, Brunetto MR, Verme G, Rizzetto M, Bonino F (1991) Hepatitis B virus replication modulates pathogenesis of hepatitis D virus in chronic hepatitis D. Hepatology 13:413–416

    Article  PubMed  CAS  Google Scholar 

  31. Wang D, Pearlberg J, Liu YT, Ganem D (2001) Deleterious effects of hepatitis delta virus on host cell proliferation. J Virol 75:3600–3604

    Article  PubMed  CAS  Google Scholar 

  32. Wang SY, Wu JC, Chiang TY, Huang YH, Su CW, Sheen IJ (2007) Positive selection of hepatitis delta antigen in chronic hepatitis D patients. J Virol 81:4438–4444

    Article  PubMed  CAS  Google Scholar 

  33. Wang Y, Menne S, Baldwin BH, Tennant BC, Gerin JL, Cote PJ (2004) Kinetics of viremia and acute liver injury in relation to outcome of neonatal woodchuck hepatitis virus infection. J Med Virol 72:406–415

    Article  PubMed  Google Scholar 

  34. Wang Y, Menne S, Jacob JR, Tennant BC, Gerin JL, Cote PJ (2003) Role of type 1 versus type 2 immune responses in liver during the onset of chronic woodchuck hepatitis virus infection. Hepatology 37:771–780

    Article  PubMed  CAS  Google Scholar 

  35. Wu JC, Chen TZ, Huang YS, Yen FS, Ting LT, Sheng WY, Tsay SH, Lee SD (1995) Natural history of hepatitis D viral superinfection: significance of viremia detected by polymerase chain reaction. Gastroenterology 108:796–802

    Article  PubMed  CAS  Google Scholar 

  36. Wu JC, Choo KB, Chen CM, Chen TZ, Huo TI, Lee SD (1995) Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet 346:939–941

    Article  PubMed  CAS  Google Scholar 

  37. Yamashiro T, Nagayama K, Enomoto N, Watanabe H, Miyagi T, Nakasone H, Sakugawa H, Watanabe M (2004) Quantification of the level of hepatitis delta virus RNA in serum, by real-time polymerase chain reaction, and its possible correlation with the clinical stage of liver disease. J Infect Dis 189:1151–1157

    Article  PubMed  CAS  Google Scholar 

  38. Zhou JH, Ferencik S, Rebmann V, Yang DL, Lu M, Roggendorf M, Grosse-Wilde H (2003) Molecular genetic and biochemical analysis of woodchuck (Marmota monax) MHC class I polymorphism. Tissue Antigens 61:240–248

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the MIUR Project 6254 on “HBV Therapeutic Vaccination: Application of Marmota Monax model”, by IRCCS Ospedale Maggiore di Milano and the Istituto Superiore di Sanità RF02.188 “Integrated National Project for the Study, the Prevention and the Treatment of the Chronic Hepatitis” (No. H95, Experimental Models line). We wish to acknowledge the staff of the animal housing (Armando Cesolini, Elfino Laconi, Andrea Giovannelli) and the study’s veterinarian (Gianluca Panzini), Romina Tomasetto and Giacinta Antonini for editing and secretarial assistance, and Mark Kanieff for linguistic revision of the manuscript.

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Authors and Affiliations

  1. Viral Hepatitis Unit, Department of Infectious, Parasitic and Immune-Mediated Disease, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    E. D’Ugo, A. Canitano, S. Catone, C. Argentini, R. Giuseppetti, S. Orobello & M. Rapicetta

  2. Pathological Anatomy Chair, Tor Vergata University, Rome, Italy

    G. Palmieri

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  1. E. D’Ugo
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  2. A. Canitano
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  3. S. Catone
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  4. C. Argentini
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  5. R. Giuseppetti
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  6. S. Orobello
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  7. G. Palmieri
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  8. M. Rapicetta
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Correspondence to M. Rapicetta.

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D’Ugo, E., Canitano, A., Catone, S. et al. Kinetics of WHV-HDV replication in acute fatal course of woodchuck hepatitis. Arch Virol 153, 2069–2076 (2008). https://doi.org/10.1007/s00705-008-0236-1

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  • DOI: https://doi.org/10.1007/s00705-008-0236-1

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