Approximately 500 million people worldwide are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV), and are therefore at an increased risk for developing fatal liver diseases such as cirrhosis and hepatocellular carcinoma. The intracellular antiviral responses induced by interferon (IFN)-α/-β and/or IFN-γ play critical roles in the pathogenesis of HBV and HCV infection, and the function of IFN-λ in the host immune response to these viruses is beginning to be revealed. A better understanding of how IFN-λ influences HBV or HCV persistence is not only important for understanding the mechanisms of chronic virus infection, but also may lead to new approaches for improved antiviral therapies.
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References
1.
AnkN, WestH, BartholdyC, ErikssonK, ThomsenAR, PaludanSR. 2006. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol, 80,9:4501–4509.
2.
AsnisGM, De La GarzaR2nd. 2006. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol, 40,4:322–335.
3.
BandiP, PagliaccettiNE, RobekMD. 2010. Inhibition of type III interferon activity by orthopoxvirus immunomodulatory proteins. J Interferon Cytokine Res, 30,3:123–134.
4.
CocciaEM, SeveraM, GiacominiE, MonneronD, RemoliME, JulkunenI, CellaM, LandeR, UzeG. 2004. Viral infection and toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol, 34,3:796–805.
5.
ConjeevaramHS, FriedMW, JeffersLJ, TerraultNA, Wiley-LucasTE, AfdhalN, BrownRS, BelleSH, HoofnagleJH, KleinerDE, HowellCD. 2006. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology, 131,2:470–477.
6.
Del Mar Fernandez de MarcoM, AlejoA, HudsonP, DamonIK, AlcamiA. 2010. The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon. FASEB J, 24,5:1479–1488.
7.
DoyleSE, SchreckhiseH, Khuu-DuongK, HendersonK, RoslerR, StoreyH, YaoL, LiuH, Barahmand-pourF, SivakumarP, ChanC, BirksC, FosterD, CleggCH, Wietzke-BraunP, MihmS, KlucherKM. 2006. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology, 44,4:896–906.
8.
FosterGR, AckrillAM, GoldinRD, KerrIM, ThomasHC, StarkGR. 1991. Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA. Proc Natl Acad Sci U S A, 88,7:2888–2892.
9.
FoyE, LiK, SumpterRJr., LooYM, JohnsonCL, WangC, FishPM, YoneyamaM, FujitaT, LemonSM, GaleMJr.2005. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci U S A, 102,8:2986–2991.
10.
FoyE, LiK, WangC, SumpterRJr., IkedaM, LemonSM, GaleMJr.2003. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science, 300,5622:1145–1148.
GriffinDE. 2003. Immune responses to RNA-virus infections of the CNS. Nat Rev Immunol, 3,6:493–502.
13.
GuidottiLG, RochfordR, ChungJ, ShapiroM, PurcellR, ChisariFV. 1999. Viral clearance without destruction of infected cells during acute HBV infection. Science, 284,5415:825–829.
14.
HeXS, JiX, HaleMB, CheungR, AhmedA, GuoY, NolanGP, PfefferLM, WrightTL, RischN, TibshiraniR, GreenbergHB. 2006. Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race. Hepatology, 44,2:352–359.
15.
HongSH, ChoO, KimK, ShinHJ, KotenkoSV, ParkS. 2007. Effect of interferon-lambda on replication of hepatitis B virus in human hepatoma cells. Virus Res, 126,1–2:245–249.
16.
HuangJ, SmirnovSV, Lewis-AntesA, BalanM, LiW, TangS, SilkeGV, PutzMM, SmithGL, KotenkoSV. 2007. Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virus. Proc Natl Acad Sci U S A, 104,23:9822–9827.
17.
KaukinenP, SillanpaaM, KotenkoS, LinR, HiscottJ, MelenK, JulkunenI. 2006. Hepatitis C virus NS2 and NS3/4A proteins are potent inhibitors of host cell cytokine/chemokine gene expression. Virol J, 3:66.
18.
KotenkoSV, GallagherG, BaurinVV, Lewis-AntesA, ShenM, ShahNK, LangerJA, SheikhF, DickensheetsH, DonnellyRP. 2003. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol, 4,1:69–77.
19.
LarkinJ, JinL, FarmenM, VenableD, HuangY, TanSL, GlassJI. 2003. Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system. J Interferon Cytokine Res, 23,5:247–257.
20.
LiK, FoyE, FerreonJC, NakamuraM, FerreonAC, IkedaM, RaySC, GaleMJr., LemonSM. 2005. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A, 102,8:2992–2997.
21.
MaherSG, SheikhF, ScarzelloAJ, Romero-WeaverAL, BakerDP, DonnellyRP, GameroAM. 2008. IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther, 7,7:1109–1115.
22.
MarcelloT, GrakouiA, Barba-SpaethG, MachlinES, KotenkoSV, MacDonaldMR, RiceCM. 2006. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology, 131,6:1887–1898.
23.
MeagerA, VisvalingamK, DilgerP, BryanD, WadhwaM. 2005. Biological activity of interleukins-28 and −29: comparison with type I interferons. Cytokine, 31,2:109–118.
24.
MihmS, FreseM, MeierV, Wietzke-BraunP, ScharfJG, BartenschlagerR, RamadoriG. 2004. Interferon type I gene expression in chronic hepatitis C. Lab Invest, 84,9:1148–1159.
25.
MordsteinM, KochsG, DumoutierL, RenauldJC, PaludanSR, KlucherK, StaeheliP. 2008. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog, 4,9:e1000151.
26.
OkuseC, RinaudoJA, FarrarK, WellsF, KorbaBE. 2005. Enhancement of antiviral activity against hepatitis C virus in vitro by interferon combination therapy. Antiviral Res, 65,1:23–34.
27.
OnoguchiK, YoneyamaM, TakemuraA, AkiraS, TaniguchiT, NamikiH, FujitaT. 2007. Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem, 282,10:7576–7581.
28.
PagliaccettiNE, ChuEN, BolenCR, KleinsteinSF, RobekMD. 2010. Lambda and alpha interferon inhibit hepatitis B virus replication through a common molecular mechanism but with different in vivo activities. Virology, 401,2:197–206.
29.
PagliaccettiNE, EduardoR, KleinsteinSH, MuXJ, BandiP, RobekMD. 2008. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J Biol Chem, 283,44:30079–30089.
30.
RaisonCL, DemetrashviliM, CapuronL, MillerAH. 2005. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs, 19,2:105–123.
31.
RauchA, KutalikZ, DescombesP, CaiT, di IulioJ, MuellerT, BochudM, BattegayM, BernasconiE, BorovickaJ, ColomboS, CernyA, DufourJF, FurrerH, GunthardHF, HeimM, HirschelB, MalinverniR, MoradpourD, MullhauptB, WitteckA, BeckmannJS, BergT, BergmannS, NegroF, TelentiA, BochudPY. 2010. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure—a genome-wide association study. Gastroenterology, 138,4:1338–13451345.e1–7.
32.
RobekMD, BoydBS, ChisariFV. 2005. Lambda interferon inhibits hepatitis B and C virus replication. J Virol, 79,6:3851–3854.
33.
RosmorducO, SirmaH, SoussanP, GordienE, LebonP, HorisbergerM, BrechotC, KremsdorfD. 1999. Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein. J Gen Virol, 80,Pt 5:1253–1262.
34.
Sarasin-FilipowiczM, OakeleyEJ, DuongFH, ChristenV, TerraccianoL, FilipowiczW, HeimMH. 2008. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A, 105,19:7034–7039.
35.
SheppardP, KindsvogelW, XuW, HendersonK, SchlutsmeyerS, WhitmoreTE, KuestnerR, GarriguesU, BirksC, RorabackJ, OstranderC, DongD, ShinJ, PresnellS, FoxB, HaldemanB, CooperE, TaftD, GilbertT, GrantFJ, TackettM, KrivanW, McKnightG, CleggC, FosterD, KlucherKM. 2003. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol, 4,1:63–68.
36.
SirenJ, PirhonenJ, JulkunenI, MatikainenS. 2005. IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol, 174,4:1932–1937.
37.
SommereynsC, PaulS, StaeheliP, MichielsT. 2008. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog, 4,3:e1000017.
38.
SuAI, PezackiJP, WodickaL, BrideauAD, SupekovaL, ThimmeR, WielandS, BukhJ, PurcellRH, SchultzPG, ChisariFV. 2002. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A, 99,24:15669–15674.
39.
SuppiahV, MoldovanM, AhlenstielG, BergT, WeltmanM, AbateML, BassendineM, SpenglerU, DoreGJ, PowellE, RiordanS, SheridanD, SmedileA, FragomeliV, MullerT, BahloM, StewartGJ, BoothDR, GeorgeJ. 2009. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet, 41,10:1100–1104.
40.
TanakaY, NishidaN, SugiyamaM, KurosakiM, MatsuuraK, SakamotoN, NakagawaM, KorenagaM, HinoK, HigeS, ItoY, MitaE, TanakaE, MochidaS, MurawakiY, HondaM, SakaiA, HiasaY, NishiguchiS, KoikeA, SakaidaI, ImamuraM, ItoK, YanoK, MasakiN, SugauchiF, IzumiN, TokunagaK, MizokamiM. 2009. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet, 41,10:1105–1109.
41.
ThomasDL, ThioCL, MartinMP, QiY, GeD, O'HuiginC, KiddJ, KiddK, KhakooSI, AlexanderG, GoedertJJ, KirkGD, DonfieldSM, RosenHR, ToblerLH, BuschMP, McHutchisonJG, GoldsteinDB, CarringtonM. 2009. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature, 461,7265:798–801.
42.
WielandS, ThimmeR, PurcellRH, ChisariFV. 2004. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A, 101,17:6669–6674.
43.
WielandSF, ChisariFV. 2005. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol, 79,15:9369–9380.
44.
WielandSF, EustaquioA, Whitten-BauerC, BoydB, ChisariFV. 2005. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A, 102,28:9913–9917.
45.
ZhangT, LinRT, LiY, DouglasSD, MaxceyC, HoC, LaiJP, WangYJ, WanQ, HoWZ. 2005. Hepatitis C virus inhibits intracellular interferon alpha expression in human hepatic cell lines. Hepatology, 42,4:819–827.
46.
ZhouL, WangX, WangYJ, ZhouY, HuS, YeL, HouW, LiH, HoWZ. 2009. Activation of toll-like receptor-3 induces interferon-lambda expression in human neuronal cells. Neuroscience, 159,2:629–637.
47.
ZhuH, ButeraM, NelsonDR, LiuC. 2005. Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. Virol J, 2:80.
