Hepatology International

, Volume 8, Supplement 2, pp 486–491 | Cite as

Basis of HBV persistence and new treatment options

  • Mark ThurszEmail author
Supplement Issue: ALPD


The majority of the morbidity and mortality associated with hepatitis B virus infection is due to viral persistence and its consequences. The heterogeneity of outcomes from HBV infection suggests that both viral and host factors influence the development of chronic infection. Study of host genetic susceptibility has revealed a number of genes including MHC class II loci and cytokine receptors, which decrease the risk of persistence. On the viral side, the replication system is adapted to generate high levels of virions without stimulating the innate immune system. Secreted viral proteins (HBsAg and HBeAg) suppress innate responses through inhibition of TLR signaling, which leads to a weak adaptive immune response with an exhausted phenotype that is incapable of inducing viral elimination. However, even when the adaptive immune system begins to take effect after HBe seroconversion, the ability of the virus to mutate and evade T and B cell-mediated responses helps to sustain persistent infection. Understanding the mechanisms of persistence is important for the design of therapeutic strategies. Although there are currently no specific drugs that target the viral minichromosome (cccDNA), it is expected that in the future we will be able to use existing drugs more effectively to eliminate the infection.


cccDNA innate immunity Adaptive immunity T cell exhaustion Genetic susceptibility 


Compliance with ethical requirements and Conflict of interest

This article does not contain any studies with human or animal subjects. The authors declare that they have no conflict of interest.


  1. 1.
    Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol 2005;34(6):1329–1339PubMedCrossRefGoogle Scholar
  2. 2.
    Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970;1(7649):695–698PubMedCrossRefGoogle Scholar
  3. 3.
    Dandri M, Locarnini S. New insight in the pathobiology of hepatitis B virus infection. Gut 2012;61(Suppl 1):6–17. doi: 10.1136/gutjnl-2012-302056.:i6-17 CrossRefGoogle Scholar
  4. 4.
    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012;1:e00049. doi: 10.7554/eLife.00049 PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Locarnini S, Zoulim F. Molecular genetics of HBV infection. Antivir Ther 2010;15(Suppl 3):3–14. doi: 10.3851/IMP1619.:3-14 PubMedCrossRefGoogle Scholar
  6. 6.
    Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009;51(3):581–592PubMedCrossRefGoogle Scholar
  7. 7.
    Urban S, Schulze A, Dandri M, Petersen J. The replication cycle of hepatitis B virus. J Hepatol 2010;52(2):282–284PubMedCrossRefGoogle Scholar
  8. 8.
    Yee LJ, Thursz MR. Hepatitis B and C. In Kaslow R, McNichol J, Hill AV, editors. Genetic Susceptibility in Infectious Disease. Oxford: OUP; 2007Google Scholar
  9. 9.
    Lin TM, Chen CJ, Wu MM, Yang CS, Chen JS, Lin CC, et al. Hepatitis B virus markers in Chinese twins. Anticancer Res 1989;9:737PubMedGoogle Scholar
  10. 10.
    Thursz M, Yee L, Khakoo S. Understanding the host genetics of chronic hepatitis B and C. Semin Liver Dis 2011;31(2):115–127PubMedCrossRefGoogle Scholar
  11. 11.
    Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, Thomas HC, Hill AV. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med 1995;332(16):1065–1069PubMedCrossRefGoogle Scholar
  12. 12.
    Thursz MR, Thomas HC, Greenwood BM, Hill AV. Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat Genet 1997;17(1):11–12PubMedCrossRefGoogle Scholar
  13. 13.
    Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 2009;41(5):591–595PubMedCrossRefGoogle Scholar
  14. 14.
    Wu TW, Chu CC, Ho TY, Chang Liao HW, Lin SK, Lin M, et al. Responses to booster hepatitis B vaccination are significantly correlated with genotypes of human leukocyte antigen (HLA)-DPB1 in neonatally vaccinated adolescents. Hum Genet 2013;132(10):1131–1139PubMedCrossRefGoogle Scholar
  15. 15.
    Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A, et al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci USA 2006;103(24):9148–9153PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351(15):1521–1531PubMedCrossRefGoogle Scholar
  17. 17.
    Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;2(8663):588–591PubMedCrossRefGoogle Scholar
  18. 18.
    Fattovich G, McIntyre G, Thursz M, Colman K, Giuliano G, Alberti A, et al. Hepatitis B virus precore/core variation and interferon therapy. Hepatology 1995;22(5):1355–1362PubMedGoogle Scholar
  19. 19.
    Lin HH, Ohto H, Etoh T, Yoneyama T, Kawana T, Mizuno M. Studies on the risk factors of intrauterine infection of hepatitis B virus. Nihon Sanka Fujinka Gakkai Zasshi 1985;37(11):2393–2400PubMedGoogle Scholar
  20. 20.
    Thursz MR, Thomas HC. Pathogenesis of chronic hepatitis B. In Thomas HC, Lemon S, Zuckerman AJ, editors. Viral Hepatitis. 3rd ed. Oxford: Blackwell; 2005. p 308–321CrossRefGoogle Scholar
  21. 21.
    Wieland SF, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 2005;79(15):9369–9380PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Postgrad Med J 2013;89(1051):294–304PubMedCrossRefGoogle Scholar
  23. 23.
    Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK, et al. Modulation of the CD8+ -T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol 2005;79(6):3322–3328PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, et al. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One 2011;6(10):e26315PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, et al. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One 2011;6(10):e26315PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Wang S, Chen Z, Hu C, Qian F, Cheng Y, Wu M, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation. J Immunol 2013;190(10):5142–5151PubMedCrossRefGoogle Scholar
  27. 27.
    Xu N, Yao HP, Lv GC, Chen Z. Downregulation of TLR7/9 leads to deficient production of IFN-alpha from plasmacytoid dendritic cells in chronic hepatitis B. Inflamm Res 2012;61(9):997–1004PubMedCrossRefGoogle Scholar
  28. 28.
    Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012;143(3):629–636PubMedCrossRefGoogle Scholar
  29. 29.
    Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol 2003;39(4):595–605PubMedCrossRefGoogle Scholar
  30. 30.
    Abe H, Ochi H, Maekawa T, Hatakeyama T, Tsuge M, Kitamura S, et al. Effects of structural variations of APOBEC3A and APOBEC3B genes in chronic hepatitis B virus infection. Hepatol Res 2009;39(12):1159–1168PubMedCrossRefGoogle Scholar
  31. 31.
    Chowdhury S, Kitamura K, Simadu M, Koura M, Muramatsu M. Concerted action of activation-induced cytidine deaminase and uracil-DNA glycosylase reduces covalently closed circular DNA of duck hepatitis B virus. FEBS Lett 2013;587(18):3148–3152PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang X, Kraft A, Broering R, Schlaak JF, Dittmer U, Lu M. Preclinical development of TLR ligands as drugs for the treatment of chronic viral infections. Expert Opin Drug Discov 2012;7(7):597–611PubMedCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2013

Authors and Affiliations

  1. 1.Hepatology & Gastroenterology SectionImperial CollegeLondonUK

Personalised recommendations