Effects of Interferon-α/β on HBV Replication Determined by Viral Load

English version České info

Interferons α and β (IFN-α/β) are type I interferons produced by the host to control microbial infections. However, the use of IFN-α to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-α/β on HBV in vivo. Interestingly, our results indicated that IFN-α/β could have opposite effects on HBV: they suppressed HBV replication when viral load was high and enhanced HBV replication when viral load was low. IFN-α/β apparently suppressed HBV replication via transcriptional and post-transcriptional regulations. In contrast, IFN-α/β enhanced viral replication by inducing the transcription factor HNF3γ and activating STAT3, which together stimulated HBV gene expression and replication. Further studies revealed an important role of IFN-α/β in stimulating viral growth and prolonging viremia when viral load is low. This use of an innate immune response to enhance its replication and persistence may represent a novel strategy that HBV uses to enhance its growth and spread in the early stage of viral infection when the viral level is low.

Vyšlo v časopise: Effects of Interferon-α/β on HBV Replication Determined by Viral Load. PLoS Pathog 7(7): e32767. doi:10.1371/journal.ppat.1002159
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002159

Souhrn

Zdroje

1. PestkaSKrauseCDWalterMR 2004 Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202 8 32

2. AaronsonDSHorvathCM 2002 A road map for those who don't know JAK-STAT. Science 296 1653 1655

3. DerSDZhouAWilliamsBRSilvermanRH 1998 Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A 95 15623 15628

4. HansenBEBusterEHSteyerbergEWLesaffreEJanssenHL 2010 Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. J Med Virol 82 1135 1142

5. XuZYenTSWuLMaddenCRTanW 2002 Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J Virol 76 2579 2584

6. WuJMengZJiangMZhangETripplerM 2010 Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 129 363 374

7. LeamanDWChawla-SarkarMJacobsBVyasKSunY 2003 Novel growth and death related interferon-stimulated genes (ISGs) in melanoma: greater potency of IFN-beta compared with IFN-alpha2. J Interferon Cytokine Res 23 745 756

8. YangPLAlthageAChungJChisariFV 2002 Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci U S A 99 13825 13830

9. WielandSFGuidottiLGChisariFV 2000 Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. J Virol 74 4165 4173

10. QuasdorffMProtzerU 2010 Control of hepatitis B virus at the level of transcription. J Viral Hepat 17 527 536

11. UngerTShaulY 1990 The X protein of the hepatitis B virus acts as a transcription factor when targeted to its responsive element. EMBO J 9 1889 1895

12. MaguireHFHoefflerJPSiddiquiA 1991 HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252 842 844

13. LinWJLiJLeeYFYehSDAltuwaijriS 2003 Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. J Biol Chem 278 9353 9360

14. GuoWTBellKDOuJH 1991 Characterization of the hepatitis B virus EnhI enhancer and X promoter complex. J Virol 65 6686 6692

15. ChenMHiengSQianXCostaROuJH 1994 Regulation of hepatitis B virus ENI enhancer activity by hepatocyte-enriched transcription factor HNF3. Virology 205 127 132

16. KosovskyMJHuanBSiddiquiA 1996 Purification and properties of rat liver nuclear proteins that interact with the hepatitis B virus enhancer 1. J Biol Chem 271 21859 21869

17. WarisGSiddiquiA 2002 Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function. J Virol 76 2721 2729

18. GuidottiLGMorrisAMendezHKochRSilvermanRH 2002 Interferon-regulated pathways that control hepatitis B virus replication in transgenic mice. J Virol 76 2617 2621

19. DarnellJEJrKerrIMStarkGR 1994 Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264 1415 1421

20. RadaevaSJarugaBHongFKimWHFanS 2002 Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes. Gastroenterology 122 1020 1034

21. AsabeSWielandSFChattopadhyayPKRoedererMEngleRE 2009 The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 83 9652 9662

22. KumarMJungSYHodgsonAJMaddenCRQinJ 2011 Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. J Virol 85 987 995

23. WeiCNiCSongTLiuYYangX 2010 The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J Immunol 185 1158 1168

24. WangHRyuWS 2010 Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog 6 e1000986

25. YuSChenJWuMChenHKatoN 2010 Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3. J Gen Virol 91 2080 2090

26. ZhengYChenWLLouieSGYenTSOuJH 2007 Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 45 16 21

27. ZhengYLiJJohnsonDLOuJH 2003 Regulation of hepatitis B virus replication by the ras-mitogen-activated protein kinase signaling pathway. J Virol 77 7707 7712

28. SirDTianYChenWLAnnDKYenTS 2010 The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A 107 4383 4388

29. LoebKRJeromeKRGoddardJHuangMCentA 2000 High-throughput quantitative analysis of hepatitis B virus DNA in serum using the TaqMan fluorogenic detection system. Hepatology 32 626 629