Advances in hepatitis C virus vaccines, part one: Advances in basic knowledge for hepatitis C virus vaccine design

Expert Opinion on Therapeutic Patents

Volumn 21, Issue 12, 2011, Pages 1811-1830

  Roohvand, Farzin ^a,b   Kossari, Niloufar ^c  

^a PASTEUR INSTITUTE OF IRAN   (Iran)

^b INSTITUT PASTEUR   (France)

^c LABORATOIRE DES SCIENCES DU CLIMAT ET DE L ENVIRONNEMENT   (France)

Author keywords

HCV; HCV ARFP; HCV immunology; HCV proteins; HCV vaccine immunosuppression; JFH1

Indexed keywords

ALPHA INTERFERON; ANTIVIRUS AGENT; CD27 ANTIGEN; CD45RA ANTIGEN; CD81 ANTIGEN; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR7; DNA VACCINE; GLYCOPROTEIN E1; GLYCOPROTEIN E2; HEPATITIS C VACCINE; HLA B27 ANTIGEN; INTERLEUKIN 12; INTERLEUKIN 28B; INTERLEUKIN 7 RECEPTOR; JANUS KINASE; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; NEUTRALIZING ANTIBODY; NONSTRUCTURAL PROTEIN 2; NONSTRUCTURAL PROTEIN 3; NONSTRUCTURAL PROTEIN 4B; NONSTRUCTURAL PROTEIN 5A; RECOMBINANT E1 VACCINE; UNCLASSIFIED DRUG; VIROPORIN P7; VIRUS PROTEIN; VIRUS VACCINE;

ADAPTIVE IMMUNITY; ANTIGEN BINDING; ANTIGEN PRESENTING CELL; APOPTOSIS; BINDING SITE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL CULTURE; CELL FUNCTION; CELLULAR IMMUNITY; CYTOKINE PRODUCTION; DRUG DESIGN; DRUG FORMULATION; FATTY LIVER; HEPATITIS C; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNITY; IMMUNIZATION; IMMUNOLOGY; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; IN VITRO STUDY; IN VIVO STUDY; LIVER CIRRHOSIS; MACROPHAGE ACTIVATION; MAJOR HISTOCOMPATIBILITY COMPLEX; NATURAL KILLER CELL; NONHUMAN; OPEN READING FRAME; PASSIVE IMMUNIZATION; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN INTERACTION; REVIEW; RNA REPLICATION; SIGNAL TRANSDUCTION; TH1 CELL; TH2 CELL; VACCINATION; VIRAL CLEARANCE; VIRUS CELL INTERACTION; VIRUS CORE; VIRUS GENE; VIRUS REPLICATION;

ACUTE DISEASE; ANIMALS; CELLS, CULTURED; DRUG DESIGN; HEPACIVIRUS; HEPATITIS C; HEPATITIS C, CHRONIC; HUMANS; MODELS, ANIMAL; VIRAL HEPATITIS VACCINES;

EID: 81855190655     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2011.630662     Document Type: Review

References (185)

1. Kumar V, Das S, Jameell S. The biology and pathogenesis of hepatitis viruses. Curr Sci 2010;98(3):312-25
2. Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000;284:450-6
3. Tan S-L. Hepatitis C viruses: genomes and molecular biology. Horizon Biosci 2006
4. Hepatitis C. World Health Organization. Fact sheet N 164 June 2011. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/index.html [Last accessed in 22 July 2011]
5. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007;13:2436-41
6. Feinstone SM, Kapikian AZ, Purcell RH, et al. Transfusion-associated hepatitis not due to viral hepatitis type A or B. N Engl J Med 1975;292:767-70
7. Alter MJ, Gerety RJ, Smallwood LA, et al. Sporadic non-A non-B hepatitis: frequency and epidemiology in an urban U.S. population. J Infect Dis 1982;145:886-93
8. Rauch A, Rickenbach M, Weber R, et al. Un safe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study. Clin Infect Dis 2005;41:395-402
9. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-62
10. Chiron Corp. NANBV diagnostics and vaccines. EP0318216; 1989
11. Simmonds P, Bukh J, Combet C, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005;42(4):962-73
12. US Health. Cloned genomes of infectious hepatitis C viruses and uses thereof. US7201911; 2007
13. US Health. Cloned genome of infectious hepatitis C virus of genotype 2a and uses thereof. WO0075338; 2000
14. US Health. Nucleotide and deduced amino acid sequences of the envelope 1 and core genes of isolates of hepatitis C virus and the use of reagents derived from these sequences in diagnostic methods and vaccines. US7070790; 2006
15. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17(2):107-15
16. Lindenbach BD, Evans MJ, Syder AJ, et al. Complete replication of hepatitis C virus in cell culture. Science 2005;309:623-6
17. Ploss A, Evans MJ, Gaysinskaya VA, et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 2009;457(7231):882-6
18. Zhang H, Rothwangl K, MesecarAD, et al. Lamiridosins, hepatitis C virus entry inhibitors from lamium album. J Nat Prod 2009;72(12):2158-62
19. NY Financial International Corp. Compositions and methods for treatment ofliver disease. WO2008100547; 2008
20. Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006;55(9):1350-9
21. Sullivan SD, Jensen DM, Bernstein DE, et al. Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C. Am J Gastroenterol 2004;99(8):1490-6
22. Houghton M, Abrignani S. Prospects for a vaccine against HCV virus. Nature 2005;436(7053):961-6
23. Stoll-Keller F, Barth H, Fafi-Kremer S, et al. Development of Hepatitis C virus vaccines: Challenges and progress. Expert Rev Vaccines 2009;8(3):333-45
24. Tripep AB. Transgenic mouse models of hepatitis C virus (HCV) and identification of HCV therapeutics. US2008295185; 2008
25. Mercer DF, Schiller DE, Elliott JF, et al. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 2001;7:927-33
26. Tokyo Metropolitan Org Med Res and Toray Industries. Nucleic acid construct containing full-length genome of human Hepatitis C virus recombinant full-length virus genome replicative cell having the nucleic acid construct transferred thereinto and method of constructing hepatitis C viral particles. WO2005080575; 2005
27. Houghton M. Discovery of the hepatitis C virus. Liver Int 2009;29(s1):82-8
28. Sen G. Viruses and interferons. Annu Rev Microbiol 2001;55:255-81
29. Ishii S, Koziel JM. Immune responses during acute and chronic infection with hepatitis C virus. Clin Immunol 2008;128:133-47
30. Zhang X, Dou J, Germann MW. Characterization of the cellular immune response in hepatitis C virus infection. Med Res Rev 2009;29(6):843-66
31. Hiroishi K, Eguchi J, Ishii S, et al. Immune response of cytotoxic T lymphocytes and possibility of vaccine development for hepatitis C virus infection. J Biomed Biotechnol 2010; Article ID 263810
32. Holz HL, Warren A, Le Couteur DG, et al. CD8+ T cell tolerance following antigen recognition on hepatocytes. J Autoimmun 2010;34:15-22
33. Bertolino P, Bowen D, McCaughan G. Immunological parameters determining adaptive immune responses to hepatitis C virus infection. In: Jirillo E, editor. The use of IFNs in HCV disease: from biology to clinical application. Springer; NY: 2007. p. 339-70
34. Univ Northeastern Ohio. Compositions and methods for modulating immunogenic responses by activating dendritic cells. WO2010120897; 2010
35. US Gov Health & Human Serv. Inducing a T cell response with recombinant pestivirus replicons or recombinant pestivirus replicon-transfected dendritic cellS. WO2004092386; 2004
36. Charles JD, Elizabeth BL, Yuk FL. Immunotherapy of virus infection. US2010143405; 2010
37. Chiron Corp. HCV immunoassays employing C domain antigens. US5350671; 1994
38. Chiron Corp. Novel Hepatitis C E1 and E2 truncated polypeptides and methods of obtaining the same. WO9604301; 1996
39. Chiron Corp. Hepatitis C virus asialoglycoproteins. WO9533053; 1995
40. Biomerieux SA and Inst Nat Sante Rech Med. Composition comprising specific non-structural proteins of hepatitis C virus, useful as prophylactic or therapeutic vaccines, also related expression vectors, microorganisms and antibodies. FR2855758; 2004
41. United Biomedical, Inc. Linear and branched peptides effective in diagnosing and detecting non-A, non-B hepatitis. US5639594; 1997
42. Akzo Nobel NV. Hepatitis C virus (HCV) non-structural-3 peptides, antibodies thereto and methods for the detection of HCV. WO9413699; 1994
43. Peking University People S Hospital. Anti-HCV vaccine and preparation methods and uses thereof US2010310605; 2010
44. Transgene SA. Hepatitis C virus non structural fusion protein. MX2008011361; 2008
45. Smyk-Pearson S, Tester IA, Lezotte D, et al. Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: implications for vaccine design. J Infect Dis 2006;194(4):454-63
46. Chiron, Inc. Novel HCV non-structural polypeptides. US2006057164; 2006
47. Okairos AG Switzerland. Simian adenovirus nucleic acid- and amino acid-sequences, vectors containing same, and uses there of WO2010086189; 2010
48. Colloca S, Folgori A, LAHM A. Hepatitis C virus nucleic acid vaccine. US2009035277; 2009
49. Transgene SA. Composition comprising the polyprotein NS3/NS4 and the polypeptide NS5B of HCV, expression vectors including the corresponding nucleic sequences and their therapeutic use. US2007269460; 2007
50. Dahari H, Feinstone S, Major ME. Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins. Gastroenterology 2010;139(3):965-74
51. Chiron Corp. NANBV diagnostics and vaccines. US6150087; 2000
52. Chiron Corp. NANBV diagnostics and vaccines. US6346375; 2002
53. Chiron Corp. NANBV diagnostics and vaccines. EP0388232; 2005
54. GlobeImmune, Inc. Yeast-based therapeutic for chronic hepatitis C infection. US2010150963; 2010
55. Novartis Vaccines & Diagnostic. Conserved motif of hepatitis C virus E2/NS1 region. US0823980; 1997
56. Chiron Corp. Immunoassays for anti-HCV antibodies using antigens with conformational epitopes. WO9401778; 1994
57. Innogenetics NV. HCV compositions. WO2004041853; 2004
58. Innogenetics NV. Immunodominant human T-cell epitopes of hepatitis C virus. WO9512677; 1995
59. Epimmune, Inc. Inducing cellular immune responses to hepatitis C virus using peptide and nucleic acid compositions. WO0121189; 2001
60. Scripps Research Inst. Peptides for inducing cytotoxic T lymphocyte responses to hepatitis C virus. WO9525122; 1995
61. Innogenetics N.V. and IDM Pharma, Inc. Peptides for inducing a CTL and/or HTL responses to Hepatitis C virus. WO118626A2; 2005
62. Lauer GM, Barnes E, Lucas M, et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 2004;127(3):924-36
63. Schulze zurWiesch J, Lauer GM, Day CL, et al Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J Immunol 2005; 175 (6) 3603-13
64. Dazert E, Neumann-Haefelin C, Bressanelli S, et al. Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest 2009;119(2):376-86
65. Wedemeyer H, He X-S, Nascimbeni M, et al. Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 2002;169(6):3447-58
66. Cooper S, Erickson AL, Adams EJ, et al. Analysis of a successful immune response against hepatitis C virus. Immunity 1999;10(4):439-49
67. Lasarte J-J, Garcia-Granero M, Lopez A, et al. Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C. Hepatology 1998;28(3):815-22
68. Urbani S, Amadei B, Fisicaro P, et al. Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology 2006;44:126-39
69. Day CL, Seth NP, Lucas M, et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J Clin Invest 2003;112(6):831-42
70. Frisch J, Tauber E, Buerger V, et al. HCV vaccines for chronic HCV patients. US2010322972; 2010
71. Chiron Corp. Hepatitis C virus multi copy epitope fusion antigens. US6428792; 2002
72. Epimmune, Inc. Inducing cellular immune responses to Hepatitis C virus using peptide and nucleic acid compositions. WO0121189; 2001
73. Arashkia A, Roohvand F, Memarnejadian A, et al. Construction of HCV-polytope vaccine candidates harbouring immune-enhancer sequences and primary evaluation of their immunogenicity in BALB/c mice. Virus Genes 2010;40(1):44-52
74. Memarnejadian A, Roohvand F, Arashkia A, et al. Polytope DNA vaccine development against hepatitis C virus: a streamlined approach from in silico design to in vitro and primary in vivo analyses in BALB/c mice. Protein Pept Lett 2009;16(7):842-50
75. Memarnejadian A, Roohvand F. Fusion of HBsAg and prime/boosting augment Th1 and CTL responses to HCV polytope DNA vaccine. Cell Immunol 2010;261(2):9
76. McLauchlan J. Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes. J Viral Hepat 2000;7:2-14
77. Roohvand F, Maillard P, Lavergne JP, et al. Initiation of hepatitis C virus infection requires the dynamic microtubule network: role of the viral nucleocapsid protein. J Biol Chem 2009;284(20):13778-91
78. Schulzezur WJ, Schmitz H, Borowski E, et al. The proteins of the Hepatitis C virus: their features and interactions with intracellular protein phosphorylation. Arch Virol 2003;148:1247-67
79. Piodi A, Chouteau P, Lerat H, et al. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology 2008;48:16-27
80. Fishman SL, Factor SH, Balestrieri C, et al. Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res 2009;15:3205-13
81. Soguero C, Joo M, Chianese-Bullock KA, et al. Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol 2002;76(18):9345-54
82. Miyoshi H, Fujie H, Shintani Y, et al. Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression. J Hepatol 2005;43:757-63
83. Lin W, Kim SS, Yeung E, et al. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol 2006;80:9226-35
84. Tsai S, Chen Y, Chen M. Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity. Gastroenterology 1998;115:954
85. Christie JM, Chapel H, Chapman RW, et al. Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus. Hepatology 1999;30:1037
86. US Health. Hepatitis C virus core peptide for stimulation of cytotoxic T lymphocytes and diagnosis of HCV exposure. WO9527733; 1995
87. Glaxo Group Ltd. Immunogenic compositions. US2009232847; 2009
88. CSL Ltd and Chiron Corp. Vaccine compositions. US2010047271; 2010
89. Pasteur Merieux Serums Vacc. Vaccine composition for preventing or treating hepatitis. US2002034734; 2002
90. Roohvand F, Aghasadeghi MR Sadat SM, et al. HCV core protein immunization with Montanide/CpG elicits strong Th1/Th2 and long-lived CTL responses. Biochem Biophys Res Commun 2007;354(3):641-9
91. Green Peptide Co. Ltd. Peptide derived from hepatitis C virus. US2010292138; 2010
92. Brierley I. Ribosomal frame-shifting on viral RNAs. J Gen Virol 1995;76:1885-92
93. Walewski JL, Keller TR, Stump DD, et al. Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame. RNA 2001;7:710-21
94. Vassilaki N, Mavromara P. The HCV ARFP/F/Core +1 protein: production and functional analysis of an unconventional viral product. IUBMB Life 2009;61(7):739-52
95. Pasteur Institut. Novel HCV Core +1 protein, methods for diagnosis of HCV infections, prophylaxis and for screening of anti-HCV agents. WO2005005468; 2005
96. Transgene and Centre Nat Rech Scient. Mutated nucleotide sequences of the hepatitis C virus. WO2006134280; 2006
97. Branch AD, Walewski JL, Stump DD. Alternate reading frame polypeptides derived from hepatitis C and methods of their use. WO2005010035; 2005
98. Bullock TN, Eisenlohr LC. Ribosomal scanning past the primary initiation codon as a mechanism for expression of CTL epitopes encoded in alternative reading frames. J Exp Med 1996;184(4):1319-29
99. Okairos AG. A vaccine for the prevention and therapy of HCV vaccine. WO2009146902; 2009
100. Helle F, Wychowski C, Vu-Dac N, et al. Cyanovirin-n inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 2006;281:25177-83
101. US Gov Health & Human Serv. Genomic nucleic acid sequence for cyanovirin-N (CV-N) and signal peptide there of. WO2007005766; 2007
102. Osel, Inc. Modified cyanovirin-N (CV-N) polypeptide. WO2006083516; 2006
103. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med 2002;195:43-9
104. LogvinoffC, Major ME, Oldach D, et al. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci USA 2004;101(27):10149-54
105. Prentoe J, Jensen TB, Meuleman P, et al. Hypervariable region 1 differentially impacts viability of hepatitis C virus strains of genotypes 1 to 6 and impairs virus neutralization. J Virol 2011;85(5):2224-34
106. von HT, Yoon JC, Alter H, et al. Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo. Gastroenterology 2007;132(2) :667-78
107. Helle F, Goffard A, Morel V, et al. The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein. J Virol 2007;81(15):8101-11
108. Agnello V, Abel G, Elfahal M, et al. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 1999;96(2):12766-71
109. EPIXIS. Method for enhancing the potency of HCV neutralizing antibodies. WO2006103493; 2006
110. Chiron Corp. HCV E1E2 vaccine compositions. US2009258033; 2009
111. Univ Francois Rabelais de Tour (FR). Novel fusion proteins and use there of for preparing hepatitis C vaccines. WO2009153518; 2009
112. Leroux-Roels G, Batens AH, Desombere I, et al. Immunogenicity and tolerability of intradermal administration of an HCV E1-based vaccine candidate in healthy volunteers and patients with resolved or ongoing chronic HCV infection. Hum Vaccin 2005;1(2):61-5
113. Novartis Vaccines & Diagnostic. Eliciting HCV-specific antibodies. US2008095800; 2008
114. US Health. Surface targeted expression of a modified hepatitis C virus envelope protein. WO9966033; 1999
115. Innogenetics NV. Recombinant vectors for producing HCV envelope proteins. EP1211315; 2002
116. Innogenetics. Purified hepatitis C virus envelope proteins for diagnostic and therapeutic use. US20010260699; 2005
117. Scripps Research Inst. HCV neutralizing epitopes. US2010104555; 2010
118. Scripps Research Inst. Mutant hepatitis C virus E2 polypeptide for HCV treatment. WO2010047829; 2010
119. Genmab AS. Anti-hepatitis C virus antibody and uses there of US2009104188; 2009
120. Univ Leland Stanford Junior. Prevention and treatment of HCV infection employing antibodies directed against conformational and linear epitopes. WO2006041866; 2006
121. KubanekBernard. Human monoclonal antibody against hepatitis c virus E2 glycoprotein. US2004071710; 2004
122. Zhang P, Zhong L, Struble EB, et al. Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity. Proc Natl Acad Sci USA 2009;106(18):7537-41
123. Perotti M, Mancini N, Diotti RA, et al. Identification of a broadly cross-reacting and neutralizing human monoclonal antibody directed against the hepatitis C virus E2 protein. J Virol 2008;82(2):1047-52
124. Meunier J-C, Russell RS, Goossens V, et al. Isolation and characterization of broadly neutralizing human monoclonal antibodies to the E1 glycoprotein of hepatitis C virus. J Virol 2008;82(2):966-73
125. Law M, Maruyama T, Lewis J, et al. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 2008;14:25-7
126. David R. Use of HCV P7 protein. US2006252918; 2006
127. Univ Oxford. Use ofiminosugar derivatives to inhibit ion channel activity. KR20050092103; 2005
128. Pietschmann T, Kaul A, Koutsoudakis G, et al. Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc Natl Acad Sci USA 2006;103:7408-13
129. Istituto Di Ricerche Di Biologia Molecolare. HCV NS2/3 fragments and uses there of. US2004054134; 2004
130. Uebelhoer L, Han J-H, Callendret B, et al. Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness. PLoS Pathog 2008;4(9):e1000143
131. Tibotec Pharm Ltd. HCV NS3-3 serine protease inhibitors. EP1881002 and EP1881001; 2008
132. Vertex Pharma. HCV NS3-NS4A protease inhibition using VX-950, also known as telaprevir. US2011059886;2011
133. Sharma SD. Hepatitis C virus: molecular biology & current therapeutic options. Indian J Med Res 2010;131:17-34
134. Innogenetics NV. HCV NS3 proteins and nucleic acids. EP1555270; 2005
135. Tripep AB. Hepatitis C virus codon optimized non-structural NS3/4A fusion gene. US2010104592; 2010
136. Tripep AB. Immunogen platform. US2009214593; 2009
137. Blight KJ. Allelic variation in the hepatitis C virus NS4B protein dramatically influences RNA replication. J Virol 2007;81:5724-36
138. Innogenetics NV. Hepatitis C virus peptides obtained from the NS4 coding region and their use in diagnostic assays. US6165730; 2000
139. Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. Plos Pathog 2008;4:e1000032
140. Kriegs M, Burckstummer T, Himmelsbach K, et al. The hepatitis C virus non structural NS5A protein impairs both the innate and adaptive hepatic immune response in vivo. J Biol Chem 2009;284:28343-51
141. Lemm JA, O'Boyle D, Liu M, et al. Identification of hepatitis C virus NS5A inhibitors. J Virol 2010;84(1):482-91
142. Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 1995;15(1):41-63
143. Centocor Ortho Biotech Product and Medivir A. Phosphoramidate derivatives ofnucleosides. EP2166016; 2010
144. Lloyd AR, Jagger E, Post JJ, et al. Host and viral factors in the immunopathogenesis of primary hepatitis C virus infection. Immunol Cell Biol 2007;85:24-32
145. PestkaJM, Zeisel MB, Blaser E, et al. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci USA 2007;104:6025-30
146. Youn JW, Park SH, Lavillette D, et al. Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee. Hepatology 2005;42(6):1429-36
147. Osburn WO, Fisher BE, Dowd KA, et al. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology 2010;138(1):315-24
148. Grant MD. Anti-idiotypic antibody and its use in diagnosis and therapy of hepatitis C virus related diseases. US2004146857; 2004
149. Grakoui A, Shoukry NH, Woollard DJ, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003;302:659-62
150. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005;436:946-52
151. Semmo N, Day CL, Ward SM, et al. Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection. Hepatology 2005;41(5):1019-28
152. Neumann-Haefelin C, Thimme R. Impact of the genetic restriction of virus-specifi c T-cell responses in hepatitis C virus infection. Genes Immun 2007;8:181-92
153. Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461(7265):798-801
154. Randall G, Chen L, Panis M, et al. Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology 2006;131:1584-91
155. Univ California. CD127 expression inversely correlates with FOXP3 and suppressive function of CD4+ tregs. WO2007140472; 2007
156. Merck & Co Inc. Enhanced first generation adenovirus vaccines expressing codon optimized HIV1-GAG POL NEF and modifications. WO0222080; 2002
157. Folgori A, Capone S, Ruggeri L, et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 2006;12(2):190-7
158. Angeletti P Inst Richerche Bio. Hepatitis C virus nucleic acid vaccine. US2009035277; 2009
159. Zubkova I, Choi YH, Chang E, et al. T-cell vaccines that elicit effective immune responses against HCV in chimpanzees may create greater immune pressure for viral mutation. Vaccine 2009;27(19):2594-602
160. Frazier AD, Zhang CL, Ni L, et al. Programmed death-1 affects suppressor ofcytokine signaling-1 expression in T cells during hepatitis C infection. Viral Immunol 2010(5):487-9
161. Zhang Y, Ma CJ, Ni L, et al. Cross-talk between programmed death-1 and suppressor ofcytokine signaling-1 in inhibition ofIL-12 production by monocytes/macrophages in hepatitis C virus infection. J Immunol 2011;186(5):3093-103
162. Yonkers NL, Sieg S, Rodriguez B, Anthony DD. Reduced naive CD4 T cell numbers and impaired induction of CD27 in response to T cell receptor stimulation reflect a state of immune activation in chronic hepatitis C virus infection. J Infect Dis 2011;203(5):635-45
163. Smyk Pearson S, Golden Mason L, Klarquist J, et al. Functional suppression by FoxP31CD41CD25(high) regulatory T cells during acute hepatitis C virus infection. J Infect Dis 2008;197:46-57
164. Sturm N, Thelu MA, Camous X, et al. Characterization and role of intra-hepatic regulatory T cells in chronic hepatitis C pathogenesis. J Hepatol 2010;53(1):25-35
165. Buschle M, Frisch J, Klade C, et al. HCVvaccines. US2009130135; 2009
166. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, et al. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ Tcells during acute HCV infection, irrespective of clinical outcome. J Virol 2008;82:3154-60
167. Lanford RE, Guerra B, Chavez D, et al. Cross-genotype immunity to hepatitis C virus. J Virol 2004;78:1575-81
168. Garcia F Jr, Garcia F, Roldan C, et al. Detection of HCV and GBV-CHGV RNA in peripheral blood mononuclear cells of patients with chronic type C hepatitis. Microbios 2000;103:7-15
169. Inst Nat Sante Rech Med. Novel human hepatoma lines, methods for obtaining same and uses there of. WO03004627; 2003
170. Hvidover Hospital. Adaptive mutations allow establishment ofJFH1-based cell culture systems for Hepatitis C Virus genotype 4A. WO2008125119; 2008
171. Hvidovre Hospital. Efficient cell culture system for hepatitis C virus genotype 2b. WO2010017818; 2010
172. Hvidovre Hospital. Efficient cell culture system for hepatitis C Virus genotype 5A. WO2008141651; 2008
173. Hvidovre Hospital. Efficient cell culture system for hepatitis C Virus genotype 6A. WO2009080052; 2009
174. Hvidovre Hospital. Efficient cell culture system for hepatitis C Virus genotype 7a. WO2010017819; 2010
175. Hidovert Hospital. Efficient cell culture system for hepatitis C virus genotype 1A and 1B. WO2009080053; 2009
176. Scheel TK, Gottwein JM, Jensen TB, et al. Development ofJFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization. Proc Natl Acad Sci USA 2008;105(3):997-1002
177. Postech Acad Ind found. An efficiently replicartive Hepatitis C Virus mutant, a HCV mutant comprising reporter gene, a method of preparing of HCV vaccine using the same and a method of screening anti HCV composition the same. WO2008133468; 2008
178. Hvidovre Hospital. Hepatitis C virus expressing reporter tagged NS5A protein. WO2010037403; 2010
179. Tory Industries. Nucleic acid containing chimeric gene derived from hepatitis Type-C. WO2009131203; 2009
180. Takahashi H, Akazawa D, Kato T, et al. Biological properties of purified recombinant HCV particles with an epitope-tagged envelope. Biochem Biophys Res Commun 2010;395:565-71
181. Lerat H, Higgs M, PawlotskyJM. Animal models in the study of hepatitis C virus-associated liver pathologies. Expert Rev Gastroenterol Hepatol 2011;5(3):341-52
182. Mercer DF. Animal models for studying hepatitis C and alcohol effects on liver. World J Gastroenterol 2011;17(20):2515-19
183. Univ Rockefeller. New HCV entry factor, occludin. WO2010040001; 2010
184. Couto LB, Kolykhalov AA. Chapter 12 animal models for HCV study. In: Tan SL, editor. Hepatitis C Viruses: Genomes and Molecular Biology. Horizon Bioscience; Norfolk (UK): 2006. p. 353-74
185. Dittmer DP, Floyd RA. RNA virus vaccines and methods. WO2007094854; 2007