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http://dx.doi.org/10.4014/jmb.1708.08045

Host Innate Immunity against Hepatitis E Virus and Viral Evasion Mechanisms  

Kang, Sangmin (Korea Zoonosis Research Institute, Chonbuk National University)
Myoung, Jinjong (Korea Zoonosis Research Institute, Chonbuk National University)
Publication Information
Journal of Microbiology and Biotechnology / v.27, no.10, 2017 , pp. 1727-1735 More about this Journal
Abstract
Hepatitis E virus (HEV) infections cause epidemic or sporadic acute hepatitis, which are mostly self-limiting. However, viral infection in immunocompromised patients and pregnant women may result in serious consequences, such as chronic hepatitis and liver damage, mortality of the latter of which reaches up to 20-30%. Type I interferon (IFN)-induced antiviral immunity is known to be the first-line defense against virus infection. Upon HEV infection in the cell, the virus genome is recognized by pathogen recognition receptors, leading to rapid activation of intracellular signaling cascades. Expression of type I IFN triggers induction of a barrage of IFN-stimulated genes, helping the cells cope with viral infection. Interestingly, some of the HEV-encoded genes seem to be involved in disrupting signaling cascades for antiviral immune responses, and thus crippling cytokine/chemokine production. Antagonistic mechanisms of type I IFN responses by HEV have only recently begun to emerge, and in this review, we summarize known HEV evasion strategies and compare them with those of other hepatitis viruses.
Keywords
Hepatitis E virus; immune evasion; innate immunity; interferon;
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1 Sridhar S, Teng JLL, Chiu TH, Lau SKP, Woo PCY. 2017. Hepatitis E virus genotypes and evolution: emergence of camel hepatitis E variants. Int. J. Mol. Sci. 18: E869.   DOI
2 Pavio N, Meng XJ, Doceul V. 2015. Zoonotic origin of hepatitis E. Curr. Opin. Virol. 10: 34-41.   DOI
3 Meng XJ. 2010. Hepatitis E virus: animal reservoirs and zoonotic risk. Vet. Microbiol. 140: 256-265.   DOI
4 Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE, et al. 1991. Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology 185: 120-131.   DOI
5 Graff J, Torian U, Nguyen H, Emerson SU. 2006. A bicistronic subgenomic mRNA encodes both the ORF2 and ORF3 proteins of hepatitis E virus. J. Virol. 80: 5919-5926.   DOI
6 Kabrane-Lazizi Y, Fine JB, Elm J, Glass GE, Higa H, Diwan A, et al. 1999. Evidence for widespread infection of wild rats with hepatitis E virus in the United States. Am. J. Trop. Med. Hyg. 61: 331-335.   DOI
7 Ropp S L, T am AW, B eames B, P urdy M , Frey TK. 2000. Expression of the hepatitis E virus ORF1. Arch. Virol. 145: 1321-1337.   DOI
8 Sehgal D, Thomas S, Chakraborty M, Jameel S. 2006. Expression and processing of the hepatitis E virus ORF1 nonstructural polyprotein. Virol. J. 3: 38.   DOI
9 Suppiah S , Zhou Y , Frey TK. 2011. Lack of processing of the expressed ORF1 gene product of hepatitis E virus. Virol. J. 8: 245.   DOI
10 Graff J, Zhou YH, Torian U, Nguyen H, St Claire M, Yu C, et al. 2008. Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles. J. Virol. 82: 1185-1194.   DOI
11 Jameel S. 1999. Molecular biology and pathogenesis of hepatitis E virus. Expert Rev. Mol. Med. 1999: 1-16.
12 Smith DB, Purdy MA, Simmonds P. 2013. Genetic variability and the classification of hepatitis E virus. J. Virol. 87: 4161-4169.   DOI
13 Yamada K, Takahashi M, Hoshino Y, Takahashi H, Ichiyama K, Nagashima S, et al. 2009. ORF3 p rotein of hepatitis E virus is essential for virion release from infected cells. J. Gen. Virol. 90: 1880-1891.   DOI
14 Qi Y, Zhang F, Zhang L, Harrison TJ, Huang W, Zhao C, et al. 2015. Hepatitis E virus produced from cell culture has a lipid envelope. PLoS One 10: e0132503.   DOI
15 Shiota T, Li TC, Yoshizaki S, Kato T, Wakita T, Ishii K. 2013. The hepatitis E virus capsid C-terminal region is essential for the viral life cycle: implication for viral genome encapsidation and particle stabilization. J. Virol. 87: 6031-6036.   DOI
16 Takahashi M, Yamada K, Hoshino Y, Takahashi H, Ichiyama K, Tanaka T, et al. 2008. Monoclonal antibodies raised against the ORF3 protein of hepatitis E virus (HEV) can capture HEV particles in culture supernatant and serum but not those in feces. Arch. Virol. 153: 1703-1713.   DOI
17 Dong C, Zafrullah M, Mixson-Hayden T, Dai X, Liang J, Meng J, et al. 2012. Suppression of interferon-alpha signaling by hepatitis E virus. Hepatology 55: 1324-1332.   DOI
18 Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, et al. 2003. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J. 17: 488-490.   DOI
19 Shuai K, Liu B. 2003. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 3: 900-911.   DOI
20 Akhtar LN, Qin H, Muldowney MT, Yanagisawa LL, Kutsch O, Clements JE, et al. 2010. Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. J. Immunol. 185: 2393-2404.   DOI
21 Boost KA, Sadik CD, Bachmann M, Zwissler B, Pfeilschifter J, Muhl H. 2008. IFN-gamma impairs release of IL-8 by IL-1beta-stimulated A549 lung carcinoma cells. BMC Cancer 8: 265.   DOI
22 Huang F, Yang C, Yu W, Bi Y, Long F, Wang J, et al. 2016. Hepatitis E virus infection activates signal regulator protein alpha to down-regulate type Iinterferon. Immunol. Res. 64: 115-122.   DOI
23 Nan Y, Yu Y, Ma Z, Khattar SK, Fredericksen B, Zhang YJ. 2014. Hepatitis E virus inhibits type I interferon induction by ORF1 products. J. Virol. 88: 11924-11932.   DOI
24 Karpe YA, Lole KS. 2011. Deubiquitination activity associated with hepatitis E virus putative papain-like cysteine protease. J. Gen. Virol. 92: 2088-2092.   DOI
25 Frias-Staheli N, Giannakopoulos NV, Kikkert M, Taylor SL, Bridgen A, Paragas J, et al. 2007. Ovarian tumor domaincontaining viral proteases evade ubiquitin- and ISG15-dependent innate immune responses. Cell Host Microbe 2: 404-416.   DOI
26 Sulea T, Lindner HA, Purisima EO, Menard R. 2005. Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease? J. Virol. 79: 4550-4551.   DOI
27 Chen WC, Tseng CK, Chen YH, Lin CK, Hsu SH, Wang SN, et al. 2015. HCV NS5A up-regulates COX-2 expression via IL-8-mediated activation of the ERK/JNK MAPK pathway. PLoS One 10: e0133264.   DOI
28 Collins AS, Ahmed S, Napoletano S, Schroeder M, Johnston JA, Hegarty JE, et al. 2014. H epatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-alpha responses. J. Leukoc. Biol. 96: 255-263.   DOI
29 Munir M, Zohari S, Belak S, Berg M. 2012. Doublestranded RNA-induced activation of activating protein-1 promoter is differentially regulated by the non-structural protein 1 of avian influenza A viruses. Viral Immunol. 25: 79-85.   DOI
30 Kang SM, Won SJ, Lee GH, Lim YS, Hwang SB. 2010. Modulation of interferon signaling by hepatitis C virus non-structural 5A protein: implication of genotypic difference in interferon treatment. FEBS Lett. 584: 4069-4076.   DOI
31 Devhare PB, Desai S, Lole KS. 2016. Innate immune responses in human hepatocyte-derived cell lines alter genotype 1 hepatitis E virus replication efficiencies. Sci. Rep. 6: 26827.   DOI
32 Skaug B, Chen ZJ. 2010. Emerging role of ISG15 in antiviral immunity. Cell 143: 187-190.   DOI
33 Ortiz NE, Nijhawan RI, Weinberg JM. 2013. Acitretin. Dermatol. Ther. 26: 390-399.   DOI
34 Clark K, Plater L, Peggie M, Cohen P. 2009. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J. Biol. Chem. 284: 14136-14146.   DOI
35 Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, et al. 1999. IKK-i, a novel lipopolysaccharideinducible kinase that is related to IkappaB kinases. Int. Immunol. 11: 1357-1362.   DOI
36 Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, et al. 2004. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199: 1641-1650.   DOI
37 Gale M Jr, Foy EM. 2005. Evasion of intracellular host defence by hepatitis C virus. Nature 436: 939-945.   DOI
38 Buccheri L, Katchen BR, Karter AJ, Cohen SR. 1997. Acitretin therapy is effective for psoriasis associated with human immunodeficiency virus infection. Arch. Dermatol. 133: 711-715.   DOI
39 Li P, Kaiser P, Lampiris HW, Kim P, Yukl SA, Havlir DV, et al. 2016. Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation. Nat. Med. 22: 807-811.   DOI
40 Horner SM, Gale M Jr. 2013. Regulation of hepatic innate immunity by hepatitis C virus. Nat. Med. 19: 879-888.   DOI
41 Zhou X, Xu L, Wang W, Watashi K, Wang Y, Sprengers D, et al. 2016. Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection. J. Viral Hepat. 23: 294-304.   DOI
42 Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6: 981-988.   DOI
43 Nair VP, Anang S, Subramani C, Madhvi A, Bakshi K, Srivastava A, et al. 2016. Endoplasmic reticulum stress induced synthesis of a novel viral factor mediates efficient replication of genotype-1 hepatitis E virus. PLoS Pathog. 12: e1005521.   DOI
44 Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124: 783-801.   DOI
45 Medzhitov R. 2007. Recognition of microorganisms and activation of the immune response. Nature 449: 819-826.   DOI
46 Seth RB, Sun L, Ea CK, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 669-682.   DOI
47 Xu LG, Wang YY, Han KJ, Li LY, Z hai Z, S hu H B. 2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19: 727-740.   DOI
48 Hardy MP, McGettrick AF, O'Neill LA. 2004. Transcriptional regulation of the human TRIF (TIR domain-containing adaptor protein inducing interferon beta) gene. Biochem. J. 380: 83-93.   DOI
49 Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr. 2008. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454: 523-527.   DOI
50 Nguyen HT, Torian U, Faulk K, Mather K, Engle RE, Thompson E, et al. 2012. A naturally occurring human/ hepatitis E recombinant virus predominates in serum but not in faeces of a chronic hepatitis E patient and has a growth advantage in cell culture. J. Gen. Virol. 93: 526-530.   DOI
51 Zhu H, Dong H, Eksioglu E, Hemming A, Cao M, Crawford JM, et al. 2007. Hepatitis C virus triggers apoptosis of a newly developed hepatoma cell line through antiviral defense system. Gastroenterology 133: 1649-1659.   DOI
52 Rotondi M, Coperchini F, Chiovato L. 2013. CXCL8 in thyroid disease: from basic notions to potential applications in clinical practice. Cytokine Growth Factor Rev. 24: 539-546.   DOI
53 Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. 2003. Role of adaptor TRIF in the MyD88- independent Toll-like receptor signaling pathway. Science 301: 640-643.   DOI
54 Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. 2003. IKKepsilon a nd TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4: 491-496.
55 Eksioglu EA, Zhu H, Bayouth L, Bess J, Liu HY, Nelson DR, et al. 2011. Characterization of HCV interactions with Toll-like receptors and RIG-I in liver cells. PLoS One 6: e21186.   DOI
56 Xu L, Zhou X, Wang W, Wang Y, Yin Y, Laan LJ, et al. 2016. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFNstimulated genes. FASEB J. 30: 3352-3367.   DOI
57 Ghasemi H, Ghazanfari T, Yaraee R, Faghihzadeh S, Hassan ZM. 2011. Roles of IL-8 in ocular inflammations: a review. Ocul. Immunol. Inflamm. 19: 401-412.   DOI
58 Pichert A, Schlorke D, Franz S, Arnhold J. 2012. Functional aspects of the interaction between interleukin-8 and sulfated glycosaminoglycans. Biomatter 2: 142-148.   DOI
59 Zarogoulidis P, Katsikogianni F, Tsiouda T, Sakkas A, Katsikogiannis N, Zarogoulidis K. 2014. Interleukin-8 and interleukin-17 for cancer. Cancer Invest. 32: 197-205.   DOI
60 Hacker H, Karin M. 2006. Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006: re13.
61 Gatot JS, Gioia R, Chau TL, Patrascu F, Warnier M, Close P, et al. 2007. Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. J. Biol. Chem. 282: 31131-31146.   DOI
62 Grandvaux N, Servant MJ, tenOever B, Sen GC, Balachandran S, Barber GN, et al. 2002. Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J. Virol. 76: 5532-5539.   DOI
63 Hiscott J. 2007. Triggering the innate antiviral response through IRF-3 activation. J. Biol. Chem. 282: 15325-15329.   DOI
64 Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. 2001. Recognition of double-stranded RNA and activation of NFkappaB by Toll-like receptor 3. Nature 413: 732-738.   DOI
65 Li Z, Chen L, Liu Q. 2015. Activation of CXCL-8 transcription by hepatitis E virus ORF-1 via AP-1. Mediators Inflamm. 2015: 495370.
66 Holtmann H, Winzen R, Holland P, Eickemeier S, Hoffmann E, Wallach D, et al. 1999. Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways. Mol. Cell. Biol. 19: 6742-6753.   DOI
67 Cucinotta M, Visalli M, Aguennouz M, Valenti A, Loddo S, Altucci L, et al. 2008. Regulation of interleukin-8 gene at a distinct site of its promoter by CCAAT enhancer-binding protein homologous protein in prostaglandin E2-treated human T cells. J. Biol. Chem. 283: 29760-29769.   DOI
68 Nozell S, Laver T, Patel K, Benveniste EN. 2006. Mechanism of IFN-beta-mediated inhibition of IL-8 gene expression in astroglioma cells. J. Immunol. 177: 822-830.   DOI
69 Gusella GL, Musso T, Bosco MC, Espinoza-Delgado I, Matsushima K, Varesio L. 1993. IL-2 up-regulates but IFNgamma suppresses IL-8 expression in human monocytes. J. Immunol. 151: 2725-2732.
70 Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. 2011. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472: 481-485.   DOI
71 Nan Y , Nan G, Z hang YJ. 2014. Interferon induction by RNA viruses and antagonism by viral pathogens. Viruses 6: 4999-5027.   DOI
72 Noppert SJ, Fitzgerald KA, Hertzog PJ. 2007. The role of type I interferons in TLR responses. Immunol. Cell Biol. 85: 446-457.   DOI
73 Nan Y, Ma Z, Wang R, Yu Y, Kannan H, Fredericksen B, et al. 2014. Enhancement of interferon induction by ORF3 product of hepatitis E virus. J. Virol. 88: 8696-8705.   DOI
74 Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNAinduced innate antiviral responses. Nat. Immunol. 5: 730-737.   DOI
75 Nakhaei P, Genin P, Civas A, Hiscott J. 2009. RIG-I-like receptors: sensing and responding to RNA virus infection. Semin. Immunol. 21: 215-222.   DOI
76 Devhare PB, Chatterjee SN, Arankalle VA, Lole KS. 2013. Analysis of antiviral response in human epithelial cells infected with hepatitis E virus. PLoS One 8: e63793.   DOI
77 Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, et al. 2007. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446: 916-920.   DOI
78 Oshiumi H, Miyashita M, Matsumoto M, Seya T. 2013. A distinct role of Riplet-mediated K63-linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses. PLoS Pathog. 9: e1003533.   DOI
79 Yu C, Boon D, McDonald SL, Myers TG, Tomioka K, Nguyen H, et al. 2010. Pathogenesis of hepatitis E virus and hepatitis C virus in chimpanzees: similarities and differences. J. Virol. 84: 11264-11278.   DOI
80 Wang J, Basagoudanavar SH, Wang X, Hopewell E, Albrecht R, Garcia-Sastre A, et al. 2010. NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication. J. Immunol. 185: 1720-1729.   DOI
81 Hardy MP, Owczarek CM, Jermiin LS, Ejdeback M, Hertzog PJ. 2004. Characterization of the type I interferon locus and identification of novel genes. Genomics 84: 331-345.   DOI
82 Vilcek J. 2003. Novel interferons. Nat. Immunol. 4: 8-9.
83 Nagashima S, Takahashi M, Jirintai, Tanaka T, Yamada K, Nishizawa T, et al. 2011. A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells. J. Gen. Virol. 92: 269-278.   DOI
84 Kenney SP, Pudupakam RS, Huang YW, Pierson FW, LeRoith T, Meng XJ. 2012. The PSAP motif within the ORF3 protein of an avian strain of the hepatitis E virus is not critical for viral infectivity in vivo but plays a role in virus release. J. Virol. 86: 5637-5646.   DOI
85 Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. 2015. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15: 405-414.   DOI
86 Xi Y, D ay S L, J ackson R J, R anasinghe C. 2012 . Role of novel type Iinterferon epsilon in viral infection and mucosal immunity. Mucosal Immunol. 5: 610-622.   DOI
87 Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, et al. 2005. A critical function for type I interferons in cancer immunoediting. Nat. Immunol. 6: 722-729.   DOI
88 Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17: 189-220.   DOI
89 Swann JB, Hayakawa Y, Zerafa N, Sheehan KC, Scott B, Schreiber RD, et al. 2007. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J. Immunol. 178: 7540-7549.   DOI
90 Asselin-Paturel C, Brizard G, Chemin K, Boonstra A, O'Garra A, Vicari A, et al. 2005. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J. Exp. Med. 201: 1157-1167.   DOI
91 Honda K, Taniguchi T. 2006. IRFs: master regulators of signalling by Toll-like receptors and cytosolic patternrecognition receptors. Nat. Rev. Immunol. 6: 644-658.   DOI
92 Xu L, Wang W, Li Y, Zhou X, Yin Y, Wang Y, et al. 2017. RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus regardless of interferon production. Hepatology 65: 1823-1839.   DOI
93 Shukla P, Nguyen HT, Torian U, Engle RE, Faulk K, Dalton HR, et al. 2011. Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. Proc. Natl. Acad. Sci. USA 108: 2438-2443.   DOI
94 Fujita T, Onoguchi K, Onomoto K, Hirai R, Yoneyama M. 2007. Triggering antiviral response by RIG-I-related RNA helicases. Biochimie 89: 754-760.   DOI
95 Shukla P, Nguyen HT, Faulk K, Mather K, Torian U, Engle RE, et al. 2012. Adaptation of a genotype 3 hepatitis E virus to efficient growth in cell culture depends on an inserted human gene segment acquired by recombination. J. Virol. 86: 5697-5707.   DOI
96 Kenney SP, Meng XJ. 2015. The lysine residues within the human ribosomal protein S17 sequence naturally inserted into the viral nonstructural protein of a unique strain of hepatitis E virus are important for enhanced virus replication. J. Virol. 89: 3793-3803.   DOI
97 Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T. 1998. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 17: 1087-1095.   DOI
98 Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, et al. 2005. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772-777.   DOI
99 Weaver BK, Kumar KP, Reich NC. 1998. Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1. Mol. Cell. Biol. 18: 1359-1368.   DOI
100 Au WC, Yeow WS, Pitha PM. 2 001. Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3. Virology 280: 273-282.   DOI
101 Hiscott J, Grandvaux N, Sharma S, Tenoever BR, Servant MJ, Lin R. 2003. Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis. Ann. NY Acad. Sci. 1010: 237-248.   DOI