1887

Abstract

Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the mechanism remains unclear. Here, we found that HCV core protein inhibits HBV replication by downregulating HBx levels during coinfection in human hepatoma cells. For this effect, HCV core protein increased reactive oxygen species levels in the mitochondria and activated the ataxia telangiectasia mutated-checkpoint kinase two pathway in the nucleus, resulting in an upregulation of p53 levels. Accordingly, HCV core protein induced p53-dependent activation of seven in absentia homolog one expression, an E3 ligase of HBx, resulting in the ubiquitination and proteasomal degradation of HBx. The effect of the HCV core protein on HBx levels was accurately reproduced in both a 1.2-mer HBV replicon and HBV infection systems, providing evidence for the inhibition of HBV replication by HCV core protein. The present study may provide insights into the mechanism of HCV dominance in HBV- and HCV-coinfected patients.

Funding
This study was supported by the:
  • National Research Foundation of Korea (Award NRF-2019R1A2C2011478)
    • Principle Award Recipient: KyungLib Jang
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001701
2021-12-09
2022-01-29
Loading full text...

Full text loading...

References

  1. Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015; 479–480:672–686 [View Article] [PubMed]
    [Google Scholar]
  2. Manns MP, Buti M, Gane E, Pawlotsky J-M, Razavi H et al. Hepatitis C virus infection. Nat Rev Dis Primers 2017; 3:17006 [View Article] [PubMed]
    [Google Scholar]
  3. Arzumanyan A, Reis H, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13:123–135 [View Article] [PubMed]
    [Google Scholar]
  4. WHO Global hepatitis report 2017; 201711–14
  5. Shih YF, Liu CJ. Hepatitis C Virus and Hepatitis B Virus Co-Infection. Viruses 2020; 12:E741 [View Article] [PubMed]
    [Google Scholar]
  6. Konstantinou D, Deutsch M. The spectrum of HBV/HCV coinfection: epidemiology, clinical characteristics, viralinteractions and management. Ann Gastroenterol 2015; 28:221–228 [PubMed]
    [Google Scholar]
  7. Crespo J, Lozano JL, de la Cruz F, Rodrigo L, Rodríguez M et al. Prevalence and significance of hepatitis C viremia in chronic active hepatitis B. Am J Gastroenterol 1994; 89:1147–1151 [PubMed]
    [Google Scholar]
  8. Ohkawa K, Hayashi N, Yuki N, Hagiwara H, Kato M et al. Hepatitis C virus antibody and hepatitis C virus replication in chronic hepatitis B patients. J Hepatol 1994; 21:509–514 [View Article] [PubMed]
    [Google Scholar]
  9. Sato S, Fujiyama S, Tanaka M, Yamasaki K, Kuramoto I et al. Coinfection of hepatitis C virus in patients with chronic hepatitis B infection. J Hepatol 1994; 21:159–166 [View Article] [PubMed]
    [Google Scholar]
  10. Sagnelli E, Sagnelli C, Macera M, Pisaturo M, Coppola N. An update on the treatment options for HBV/HCV coinfection. Expert Opin Pharmacother 2017; 18:1691–1702 [View Article] [PubMed]
    [Google Scholar]
  11. Pallás JR, Fariñas-Alvarez C, Prieto D, Delgado-Rodríguez M. Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users. Eur J Epidemiol 1999; 15:699–704 [View Article] [PubMed]
    [Google Scholar]
  12. Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation 2005; 79:1132–1136 [View Article] [PubMed]
    [Google Scholar]
  13. Chu CM, Yeh CT, Liaw YF. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection. J Clin Microbiol 1998; 36:2084–2086 [View Article] [PubMed]
    [Google Scholar]
  14. Liaw Y-F, Chen Y-C, Sheen I-S, Chien R-N, Yeh C-T et al. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 2004; 126:1024–1029 [View Article] [PubMed]
    [Google Scholar]
  15. Sheen IS, Liaw YF, Chu CM, Pao CC. Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection. J Infect Dis 1992; 165:831–834 [View Article] [PubMed]
    [Google Scholar]
  16. Brotman B, Prince AM, Huima T, Richardson L, van den Ende MC et al. Interference between non-A, non-B and hepatitis B virus infection in chimpanzees. J Med Virol 1983; 11:191–205 [View Article] [PubMed]
    [Google Scholar]
  17. Liaw YF, Lin SM, Sheen IS, Chu CM. Acute hepatitis C virus superinfection followed by spontaneous HBeAg seroconversion and HBsAg elimination. Infection 1991; 19:250–251 [View Article] [PubMed]
    [Google Scholar]
  18. Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S et al. The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol 2008; 49:688–694 [View Article] [PubMed]
    [Google Scholar]
  19. Hamzaoui L, El Bouchtili S, Siai K, Mahmoudi M, Azzouz MM. Hepatitis B virus and hepatitis C virus co-infection: a therapeutic challenge. Clin Res Hepatol Gastroenterol 2013; 37:e16–20 [View Article] [PubMed]
    [Google Scholar]
  20. Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol 1993; 67:5823–5832 [View Article] [PubMed]
    [Google Scholar]
  21. Chen S-Y, Kao C-F, Chen C-M, Shih C-M, Hsu M-J et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J Biol Chem 2003; 278:591–607 [View Article] [PubMed]
    [Google Scholar]
  22. Schüttler CG, Fiedler N, Schmidt K, Repp R, Gerlich WH et al. Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein. J Hepatol 2002; 37:855–862 [View Article] [PubMed]
    [Google Scholar]
  23. Tang H, Delgermaa L, Huang F, Oishi N, Liu L et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication. J Virol 2005; 79:5548–5556 [View Article] [PubMed]
    [Google Scholar]
  24. Lucifora J, Arzberger S, Durantel D, Belloni L, Strubin M et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol 2011; 55:996–1003 [View Article] [PubMed]
    [Google Scholar]
  25. Zhao J, Wang C, Wang J, Yang X, Diao N et al. E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal degradation of the hepatitis B viral X protein. FEBS Lett 2011; 585:2943–2950 [View Article] [PubMed]
    [Google Scholar]
  26. Kim S, Lee H-S, Ji J-H, Cho M-Y, Yoo Y-S et al. Hepatitis B virus X protein activates the ATM-Chk2 pathway and delays cell cycle progression. J Gen Virol 2015; 96:2242–2251 [View Article] [PubMed]
    [Google Scholar]
  27. Yeom S, Kim SS, Jeong H, Jang KL. Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop. J Gen Virol 2017; 98:1774–1784 [View Article] [PubMed]
    [Google Scholar]
  28. Kwak J, Tiwari I, Jang KL. Hepatitis C virus core activates proteasomal activator 28γ expression via upregulation of p53 levels to control virus propagation. J Gen Virol 2017; 98:56–67 [View Article] [PubMed]
    [Google Scholar]
  29. Arora P, Kim EO, Jung JK, Jang KL. Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett 2008; 261:244–252 [View Article] [PubMed]
    [Google Scholar]
  30. Kwun HJ, Jang KL. Natural variants of hepatitis B virus X protein have differential effects on the expression of cyclin-dependent kinase inhibitor p21 gene. Nucleic Acids Res 2004; 32:2202–2213 [View Article] [PubMed]
    [Google Scholar]
  31. Chang J, Yang SH, Cho YG, Hwang SB, Hahn YS et al. Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene. J Virol 1998; 72:3060–3065 [View Article] [PubMed]
    [Google Scholar]
  32. Cha MY, Ryu DK, Jung HS, Chang HE, Ryu WS. Stimulation of hepatitis B virus genome replication by HBx is linked to both nuclear and cytoplasmic HBx expression. J Gen Virol 2009; 90:978–986 [View Article] [PubMed]
    [Google Scholar]
  33. Matsuzawa SI, Reed JC. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell 2001; 7:915–926 [View Article] [PubMed]
    [Google Scholar]
  34. Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci U S A 2002; 99:15655–15660 [View Article] [PubMed]
    [Google Scholar]
  35. Ndongo-Thiam N, Berthillon P, Errazuriz E, Bordes I, De Sequeira S et al. Long-term propagation of serum hepatitis C virus (HCV) with production of enveloped HCV particles in human HepaRG hepatocytes. Hepatology 2011; 54:406–417 [View Article] [PubMed]
    [Google Scholar]
  36. Zhou M, Zhao K, Yao Y, Yuan Y, Pei R et al. Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells. Virol Sin 2017; 32:465–475 [View Article] [PubMed]
    [Google Scholar]
  37. Feigelstock DA, Mihalik KB, Kaplan G, Feinstone SM. Increased susceptibility of Huh7 cells to HCV replication does not require mutations in RIG-I. Virol J 2010; 7:44. [View Article] [PubMed]
    [Google Scholar]
  38. Kanebratt KP, Andersson TB. HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 2008; 36:137–145 [View Article] [PubMed]
    [Google Scholar]
  39. Yeom S, Jeong H, Kim SS, Jang KL. Hepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication. J Gen Virol 2018; 99:655–666 [View Article] [PubMed]
    [Google Scholar]
  40. Kato T, Date T, Miyamoto M, Furusaka A, Tokushige K et al. Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology 2003; 125:1808–1817 [View Article] [PubMed]
    [Google Scholar]
  41. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A 2005; 102:9294–9299 [View Article] [PubMed]
    [Google Scholar]
  42. Takeuchi T, Katsume A, Tanaka T, Abe A, Inoue K et al. Real-time detection system for quantification of hepatitis C virus genome. Gastroenterology 1999; 116:636–642 [View Article] [PubMed]
    [Google Scholar]
  43. Mendy ME, Kaye S, van der Sande M, Rayco-Solon P, Waight PA et al. Application of real-time PCR to quantify hepatitis B virus DNA in chronic carriers in The Gambia. Virol J 2006; 3:23. [View Article] [PubMed]
    [Google Scholar]
  44. Severi T, Vander Borght S, Libbrecht L, VanAelst L, Nevens F et al. HBx or HCV core gene expression in HepG2 human liver cells results in a survival benefit against oxidative stress with possible implications for HCC development. Chem Biol Interact 2007; 168:128–134 [View Article] [PubMed]
    [Google Scholar]
  45. Henkler F, Hoare J, Waseem N, Goldin RD, McGarvey MJ et al. Intracellular localization of the hepatitis B virus HBx protein. J Gen Virol 2001; 82:871–882 [View Article] [PubMed]
    [Google Scholar]
  46. Kwak J, Tiwari I, Jang KL. Hepatitis C virus core activates proteasomal activator 28γ expression via upregulation of p53 levels to control virus propagation. J Gen Virol 2017; 98:56–67 [View Article] [PubMed]
    [Google Scholar]
  47. Quasdorff M, Protzer U. Control of hepatitis B virus at the level of transcription. J Viral Hepat 2010; 17:527–536 [View Article] [PubMed]
    [Google Scholar]
  48. Keasler VV, Hodgson AJ, Madden CR, Slagle BL. Enhancement of hepatitis B virus replication by the regulatory X protein in vitro and in vivo. J Virol 2007; 81:2656–2662 [View Article] [PubMed]
    [Google Scholar]
  49. Jeong H, Cha S, Jang KL. HBx natural variants containing Ser-101 instead of Pro-101 evade ubiquitin-dependent proteasomal degradation by activating proteasomal activator 28 gamma expression. J Gen Virol 2019; 100:1554–1566 [View Article] [PubMed]
    [Google Scholar]
  50. Liu C, Chuang W, Lee C, Yu M, Lu S et al. Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology 2009; 136:496–504 [View Article]
    [Google Scholar]
  51. Yu M-L, Lee C-M, Chen C-L, Chuang W-L, Lu S-N et al. Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up. Hepatology 2013; 57:2135–2142 [View Article] [PubMed]
    [Google Scholar]
  52. Belperio PS, Shahoumian TA, Mole LA, Backus LI. Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals. Hepatology 2017; 66:27–36 [View Article] [PubMed]
    [Google Scholar]
  53. Paeshuyse J, Dallmeier K, Neyts J. Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action. Curr Opin Virol 2011; 1:590–598 [View Article] [PubMed]
    [Google Scholar]
  54. Tsuge M, Hiraga N, Akiyama R, Tanaka S, Matsushita M et al. HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice. J Gen Virol 2010; 91:1854–1864 [View Article] [PubMed]
    [Google Scholar]
  55. Xu Z, Yen TSB, Wu L, Madden CR, Tan W et al. Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J Virol 2002; 76:2579–2584 [View Article] [PubMed]
    [Google Scholar]
  56. Keasler VV, Hodgson AJ, Madden CR, Slagle BL. Hepatitis B virus HBx protein localized to the nucleus restores HBx-deficient virus replication in HepG2 cells and in vivo in hydrodynamically-injected mice. Virology 2009; 390:122–129 [View Article] [PubMed]
    [Google Scholar]
  57. Park SG, Min JY, Chung C, Hsieh A, Jung G. Tumor suppressor protein p53 induces degradation of the oncogenic protein HBx. Cancer Lett 2009; 282:229–237 [View Article] [PubMed]
    [Google Scholar]
  58. Chu CM, Yeh CT, Sheen IS, Liaw YF. Acute hepatitis C virus (HCV) infection in chronic carriers of hepatitis B virus (HBV): the impact of underlying active HBV replication on persistence of HCV infection and antibody responses to HCV. Gut 2002; 51:95–99 [View Article] [PubMed]
    [Google Scholar]
  59. Biliotti E, Kondili LA, Furlan C, Ferretti G, Zacharia S et al. Acute hepatitis B in patients with or without underlying chronic HCV infection. J Infect 2008; 57:152–157 [View Article] [PubMed]
    [Google Scholar]
  60. Pan Y, Wei W, Kang L, Wang Z, Fang J et al. NS5A protein of HCV enhances HBV replication and resistance to interferon response. Biochem Biophys Res Commun 2007; 359:70–75 [View Article] [PubMed]
    [Google Scholar]
  61. Eyre NS, Phillips RJ, Bowden S, Yip E, Dewar B et al. Hepatitis B virus and hepatitis C virus interaction in Huh-7 cells. J Hepatol 2009; 51:446–457 [View Article] [PubMed]
    [Google Scholar]
  62. Sagnelli E, Coppola N, Pisaturo M, Masiello A, Tonziello G et al. HBV superinfection in HCV chronic carriers: a disease that is frequently severe but associated with the eradication of HCV. Hepatology 2009; 49:1090–1097 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001701
Loading
/content/journal/jgv/10.1099/jgv.0.001701
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error