Primary Seronegative but Molecularly Evident Hepadnaviral Infection Engages Liver and Induces Hepatocarcinoma in the Woodchuck Model of Hepatitis B

English version České info

Introduction of highly sensitive molecular assays for detection of hepatitis B virus (HBV) identified the existence of persistent occult HBV infection years after recovery from an episode of hepatitis B and in individuals exposed to HBV but without symptoms and classical markers of infection. Because HBV integrates into human DNA and is a potent human carcinogen, it is postulated that occult HBV infection can be a cause of hepatic cancer in many individuals in which the tumor origin remains currently unknown. A causative relation between occult HBV infection and hepatocarcinoma is highly challenging to investigate in humans since occult HBV persistence is rarely diagnosed with current clinical assays and cancer development takes 15–30 years. However, we have established excellent models of occult HBV infection in the eastern North American woodchucks which are naturally susceptible to a virus closely related to HBV and in which chronic infection advances to liver cancer. In the current study, exploring experimental primary occult infection in woodchucks, we proved that the silently progressing infection, which is not detectable by serological markers, can culminate in hepatocellular carcinoma and that the persisting virus remains infectious, and causes hepatitis and liver cancer when transmitted to virus-naïve hosts.

Vyšlo v časopise: Primary Seronegative but Molecularly Evident Hepadnaviral Infection Engages Liver and Induces Hepatocarcinoma in the Woodchuck Model of Hepatitis B. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004332
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004332

Souhrn

Zdroje

1. World Health Organization (2012) Hepatitis B fact sheet, 2012 revision date. W.H.O./204. World Health Organization. Geneva, Switzerland. Available: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed 31 July 2013.

2. MichalakTI, PasquinelliC, GuilhotS, ChisariFV (1994) Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 93 : 230–239.

3. RehermannB, FerrariC, PasquinelliC, ChisariFV (1996) The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 2 : 1104–1108.

4. MichalakTI (2000) Occult persistence and lymphotropism of hepadnaviral infection: insights from the woodchuck viral hepatitis model. Immunol Rev 174 : 98–111.

5. Mulrooney-CousinsPM, MichalakTI (2007) Persistent occult hepatitis B virus infection: experimental findings and clinical implications. World J Gastroenterol 13 : 5682–5686.

6. CoffinCS, MichalakTI (1999) Persistence of infectious virus in the offspring of woodchuck mothers recovered from viral hepatitis. J Clin Invest 104 : 203–212.

7. MichalakTI, PardoeIU, CoffinCS, ChurchillND, FreakeDS, et al. (1999) Occult life-long persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology 29 : 928–938.

8. CoffinCS, PhamTN, MulrooneyPM, ChurchillND, MichalakTI (2004) Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection. Hepatology 40 : 1053–1061.

9. MichalakTI, MulrooneyPM, CoffinCS (2004) Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. J Virol 78 : 1730–1738.

10. HuangYW, ChungRT (2012) Management of hepatitis B reactivation in patients receiving cancer chemotherapy. Therap Adv Gastroenterol 5 : 359–370.

11. PollicinoT, SquadritoG, CerenziaG, CacciolaI, RaffaG, et al. (2004) Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 126 : 102–110.

12. WongDKH, HuangFY, LaiCL, PoonRTP, SetoWK, et al. (2011) Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology 54 : 829–836.

13. GujarSA, Mulrooney-CousinsPM, MichalakTI (2013) Repeated exposure to trace amounts of woodchuck hepadnavirus induces molecularly evident infection and virus-specific T cell response in the absence of serological infection markers and hepatitis. J Virol 87 : 1035–1048.

14. ZerbiniA, PilliM, BoniC, FisicaroP, PennaA, et al. (2008) The characteristics of the cell-mediated immune response identify different profiles of occult hepatitis B virus infection. Gastroenterology 134 : 1470–1481.

15. ArbuthnotP, KewM (2001) Hepatitis B virus and hepatocellular carcinoma. Int J Exp Pathol 82 : 77–100.

16. TennantBC, ToshkovIA, PeekSF, JacobJR, MenneS, et al. (2004) Hepatocellular carcinoma in the woodchuck model of hepatitis B virus infection. Gastroenterology 127 : 283–293.

17. Mulrooney-CousinsPM, MichalakTI (2008) Repeated passage of wild-type woodchuck hepatitis virus in lymphoid cells does not generate cell type-specific variants or alter virus infectivity. J Virol 82 : 7540–7550.

18. BruniR, ArgentiniC, D'UgoE, GiuseppettiR, RapicellaM (1995) A PCR-based strategy for rapid mapping of hepadnavirus integrated sequences in hepatocellular carcinomas. J Virol Methods 52 : 347–360.

19. CuiH, HedborgF, HeL, NordenskjöldA, SandstedtB, et al. (1997) Inactivation of H19, an imprinted and putative tumor repressor gene, is a preneoplastic event during Wilms' tumorigenesis. Cancer Res 57 : 4469–4473.

20. JinYM, ChurchillND, MichalakTI (1996) Protease-activated lymphoid cell and hepatocyte recognition site in the preS1 domain of the large woodchuck hepatitis virus envelope protein. J Gen Virol 77 : 1837–1846.

21. MichalakTI (2007) Characteristics and consequences of experimental occult hepatitis B virus infection in the woodchuck model of hepatitis B. Curr Topics Virol 6 : 1–13.

22. BréchotC, HadchouelM, ScottoJ, FonckM, PotetF, et al. (1981) State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases. Proc Natl Acad Sci USA 78 : 3906–3910.

23. ChenJY, HarrisionTJ, LeeCS, ChenDS, ZuckermanAJ (1986) Detection of hepatitis B virus DNA in hepatocellular carcinoma. Br J Exp Pathol 67 : 279–288.

24. FaraziPA, DePinhoRA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 194 : 594–599.

25. KorbaBE, WellsF, BaldwinB, CotePJ, TennantBC, et al. (1989) Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infection. Hepatology 9 : 461–470.

26. HsuT, MöröyT, EtiembleJ, LouiseA, TrépoC, et al. (1988) Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55 : 627–635.

27. FourelG, TrepoC, BougueleretL, HengleinB, PonzettoA, et al. (1990) Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature 347 : 294–298.

28. HigashiY, TadaS, MiyaseS, HirotaK, ImamuraH, et al. (2002) Correlation of clinical characteristics with detection of hepatitis B virus X gene in liver tissue in HBsAg-negative, and HCV-negative hepatocellular carcinoma patients. Liver 22 : 374–379.

29. LaskusT, RadkowskiM, WangLF, NowickiM, RakelaJ (1999) Detection and sequence analysis of hepatitis B virus integration in peripheral blood mononuclear cells. J Virol 73 : 1235–1238.

30. KorbaBE, WellsF, TennantBC, CotePJ, GerinJL (1987) Lymphoid cells in the spleens of woodchuck hepatitis virus-infected woodchucks are a site of active viral replication. J Virol 61 : 1318–1324.

31. GujarSA, JenkinsAK, GuyCS, WangJ, MichalakTI (2008) Aberrant lymphocyte activation precedes delayed virus-specific T-cell response after both primary infection and secondary exposure to hepadnavirus in the woodchuck model of hepatitis B virus infection. J Virol 82 : 6992–7008.

32. GujarSA, MichalakTI (2009) Primary occult hepadnavirus infection induces virus-specific T-cell and aberrant cytokine responses in the absence of antiviral antibody reactivity in the woodchuck model of hepatitis B virus infection. J Virol 83 : 3861–3876.

33. AsabeS, WielandSF, ChattopadhyayPK, RoedererM, EngleRE, et al. (2009) The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 83 : 9652–9662.

34. ChallineD, ChevaliezS, PawlotskyJM (2008) Efficacy of serologic marker screening in identifying hepatitis B virus infection in organ, tissue, and cell donors. Gastroenterology 135 : 1185–1191.