Hepatitis C Virus - Proteins, Diagnosis, Treatment and New Approaches for Vaccine Development

  • Keyvani, Hossein (Department of Clinical Virology, Tehran University of Medical Sciences) ;
  • Fazlalipour, Mehdi (Department of Medical Virology, Tehran University of Medical Sciences) ;
  • Monavari, Seyed Hamid Reza (Department of Clinical Virology, Tehran University of Medical Sciences) ;
  • Mollaie, Hamid Reza (Department of Medical Virology, Tehran University of Medical Sciences)
  • Published : 2012.12.31


Background: Hepatitis C virus (HCV) causes acute and chronic human hepatitis infection and as such is an important global health problem. The virus was discovered in the USA in 1989 and it is now known that three to four million people are infected every year, WHO estimating that 3 percent of the 7 billion people worldwide being chronically infected. Humans are the natural hosts of HCV and this virus can eventually lead to permanent liver damage and carcinoma. HCV is a member of the Flaviviridae family and Hepacivirus genus. The diameter of the virus is about 50-60 nm and the virion contains a single-stranded positive RNA approximately 10,000 nucleotides in length and consisting of one ORF which is encapsulated by an external lipid envelope and icosahedral capsid. HCV is a heterogeneous virus, classified into 6 genotypes and more than 50 subtypes. Because of the genome variability, nucleotide sequences of genotypes differ by approximately 31-34%, and by 20-23% among subtypes. Quasi-species of mixed virus populations provide a survival advantage for the virus to create multiple variant genomes and a high rate of generation of variants to allow rapid selection of mutants for new environmental conditions. Direct contact with infected blood and blood products, sexual relationships and availability of injectable drugs have had remarkable effects on HCV epidemiology. Hundreds of thousands of people die each year from hepatitis and liver cancer caused by HCV virus infection. Approximately 80% of patients with acute hepatitis C progress into a chronic disease state leading to serious hepatic disorders, 10-20% of which develop chronic liver cirrhosis and hepatocellular carcinoma. The incubation period of HCV is 6-8 weeks and the infection is often asymptomatic so it is very hard to detect at early stages, making early treatment very difficult. Therefore, hepatitis C is called a "silent disease". Neutralizing antibodies are produced against several HCV proteins during infection but the virus mutates to escape from antibodies. Some patients with chronic hepatitis C may have some symptoms such as fatigue, muscle aches, nausea and pain. Autoimmune and immunecomplex-mediated diseases have also been reported with chronic HCV infection.


Hepatitis C Virus;treatment;vaccine;virus like particle


  1. Yamanaka T, Uchida M, Doi T (2002). Innate form of HCV core protein plays an important role in the localization and the function of HCV core protein. Biochemical and Biophysical Res Communications, 294, 521-7.
  2. Yang X-J, Liu J, Ye L, et al (2006). HCV NS2 protein inhibits cell proliferation and induces cell cycle arrest in the S-phase in mammalian cells through down-regulation of cyclin A expression. Virus Res, 121, 134-43.
  3. Ye L, Li J, Zhang T, et al (2012). Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells. Virus Res, 65, 65-9.
  4. Yoo D, Song C, Sun Y, et al (2010). Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus. Virus Res, 154, 48-60.
  5. Zeisel MB, Baumert TF (2006). Production of infectious hepatitis C virus in tissue culture: A breakthrough for basic and applied research. J Hepatology, 44, 436-9.
  6. Zeng J, Wu Y, Liao Q, Li L, Chen X (2012). Liver X receptors agonists impede hepatitis C virus infection in an Idol-dependent manner. Antiviral Res, 85, 36-9.
  7. Zeng R, Li G, Ling S, et al (2009). A novel combined vaccine candidate containing epitopes of HCV NS3, core and E1 proteins induces multi-specific immune responses in BALB/c mice. Antiviral Res, 84, 23-30.
  8. Zeremski M, Makeyeva J, Arasteh K, et al (2012). Hepatitis C virusspecific immune responses in noninjecting drug users. J Viral Hepat, 19, 554-9.
  9. Zhang K, Tan WJ, Deng Y, et al (2008). Development of infectious pseudo-particle harboring three subtypes hepatitis C virus glycoproteins and their application in neutralization assays. Bing Du Xue Bao, 24, 287-94.
  10. Zhao Y, Sanchez A, Nie X, et al (2008). A highly sensitive and reproducible HCV RNA hybridization method valuable for antiviral drug discovery. J Virological Methods, 151, 154-7.
  11. Zheng X, Pang M, Chan A, et al (2003). Direct comparison of hepatitis C virus genotypes tested by INNO-LiPA HCV II and TRUGENE HCV genotyping methods. J Clinical Virology, 28, 214-6.
  12. Zielonka A, Gedvilaite A, Ulrich R, et al (2006). Generation of viruslike particles consisting of the major capsid protein VP1 of goose hemorrhagic polyomavirus and their application in serological tests. Virus Res, 120, 128-37.
  13. Zuo G, Li Z, Chen L, Xu X (2007). Activity of compounds from Chinese herbal medicine Rhodiola kirilowii (Regel) Maxim against HCV NS3 serine protease. Antiviral Res, 76, 86-92.
  14. Tan Y-J, Lim S-P, Ng P, et al (2003). CD81 engineered with endocytotic signals mediates HCV cell entry: implications for receptor usage by HCV in vivo. Virology, 308, 250-69.
  15. Tanaka M, Fujiyama S, Itoh K, et al (2004). Clinical usefulness of a new hepatitis C virus RNA extraction method using specific capture probe and magnetic particle in hemodialysis patients. Ther Apher Dial, 8, 328-34.
  16. Tang J, Lee K, Bothner B, et al (2009). Dynamics and Stability in Maturation of a Virus. J Molecular Biology, 392, 803-12.
  17. Thuman-Commike PA, Greene B, Malinski JA, et al (1999). Mechanism of scaffolding-directed virus assembly suggested by comparison of scaffolding-containing and scaffolding-lacking p22 procapsids. Biophysical J, 76, 3267-77.
  18. Tobin GJ, Battles JK, Rasmussen L, et al (1995). [15] Assembly of recombinant retroviral gag precursors into pseudovirions in the baculovirus-insect cell expression system. In W A Kenneth (Ed.), Methods in Molecular Genetics, 7, 237-53
  19. Tong X, Malcolm BA (2006). Trans-complementation of HCV replication by non-structural protein 5A. Virus Res, 115, 122-30.
  20. Uno-Furuta S, Matsuo K, Tamaki S, et al (2003). Immunization with recombinant Calmette-Guerin bacillus (BCG)-hepatitis C virus (HCV) elicits HCV-specific cytotoxic T lymphocytes in mice. Vaccine, 21, 3149-56.
  21. van Oers MM (2006). Vaccines for viral and parasitic diseases produced with baculovirus vectors. In K M Bryony C. Bonning & J S Aaron (Eds.), Advances in Virus Res, 68, 193-253.
  22. Velazquez VM, Hon H, Ibegbu C, et al (2012). Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection. Hepatology, 39, 36-9.
  23. Vermehren J, Yu M-L, Monto A, et al (2011). Multi-center evaluation of the Abbott RealTime HCV Assay for monitoring patients undergoing antiviral therapy for chronic hepatitis C. J Clinical Virology, 52, 133-7.
  24. Vidalin O, Fournillier A, Renard N, et al (2000). Use of conventional or replicating nucleic acid-based vaccines and recombinant semliki forest virus-derived particles for the induction of immune responses against hepatitis C virus core and E2 antigens. Virology, 276, 259-70.
  25. Wang Y, Xia X, Li C, et al (2009). A new HCV genotype 6 subtype designated 6v was confirmed with three complete genome sequences. J Clinical Virology, 44, 195-9.
  26. Wegzyn CM, Wyles DL (2012). Antiviral drug advances in the treatment of human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV). Current Opinion in Pharmacology, 23, 450-9.
  27. Wu X, Ishaq M, Hu J, Guo D (2008). HCV NS3/4A protein activates HIV-1 transcription from its long terminal repeat. Virus Res, 135, 155-60.
  28. Roingeard P, Hourioux C, Blanchard E, et al (2004). Hepatitis C virus ultrastructure and morphogenesis. Biology of the Cell, 96, 103-8.
  29. Roldao A, Silva AC, Mellado M, et al (2011). 1.47-Viruses and Virus- Like Particles in Biotechnology: Fundamentals and Applications. In M-Y Editor-in-Chief: murray (Ed.), Comprehensive Biotechnology (Second Edition), 625-649.
  30. Roldao A, Vieira HLA, Charpilienne A, et al (2007). Modeling rotavirus-like particles production in a baculovirus expression vector system: Infection kinetics, baculovirus DNA replication, mRNA synthesis and protein production. J Biotechnology, 128, 875-94.
  31. Roohvand F, Aghasadeghi M-R, Sadat S M, et al (2007). HCV core protein immunization with Montanide/CpG elicits strong Th1/ Th2 and long-lived CTL responses. Biochemical and Biophysical Res Communications, 354, 641-9.
  32. Ruzzenenti MR, De Luigi MC, Bruni R, et al (2000). PCR testing for HCV in anti-HCV negative blood donors involved in the so called HCV +ve post-transfusion hepatitis. Transfusion Sci, 22, 161-4.
  33. Safi AZ, Waheed Y, Sadat J, et al (2012). Molecular study of HCV detection, genotypes and their routes of transmission in North West Frontier Province, Pakistan. Asian Pac J Tropical Biomedicine, 2, 532-6.
  34. Schlaphoff V, Klade CS, Jilma B, et al (2007). Functional and phenotypic characterization of peptide-vaccine-induced HCVspecific CD8+ T cells in healthy individuals and chronic hepatitis C patients. Vaccine, 25, 6793-806.
  35. Schmeding M, Kienlein S, Rocken C, et al (2010). ELISA-based detection of C4d after liver transplantation - A helpful tool for differential diagnosis between acute rejection and HCVrecurrence? Transplant Immunology, 23, 156-60.
  36. Scott Muerhoff A,J. Dawson G. (2003). Hepatitis C virus. In K M Ias (Ed.), Perspectives in Medical Virology, 10, 127-71.
  37. Shi J, Zhou L, Amblard F, et al (2012). Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors. Bioorganic and amp; Med Chemistry Letters, 22, 3488-91.
  38. Sistigu A, Bracci L, Valentini M, et al (2011). Strong CD8+ T cell antigenicity and immunogenicity of large foreign proteins incorporated in HIV-1 VLPs able to induce a Nef-dependent activation/maturation of dendritic cells. Vaccine, 29, 3465-75.
  39. Song H, Wittman V, Byers A, et al (2010). In vitro stimulation of human influenza-specific CD8+ T cells by dendritic cells pulsed with an influenza virus-like particle (VLP) vaccine. Vaccine, 28, 5524-32.
  40. Speir JA, Johnson JE (2008). Tetraviruses. In B W J M Editors-in- Chief: & M H V V Regenmortel (Eds.), Encyclopedia of Virology (Third Edition) Oxford: Academic Press. 27-37.
  41. Steinmann D, Barth H, Gissler B, et al (2004). Inhibition of hepatitis C virus-like particle binding to target cells by antiviral antibodies in acute and chronic hepatitis C. J Virol, 78, 9030-40.
  42. Nishimura Y, Kamei A, Uno-Furuta S, et al (1999). A single immunization with a plasmid encoding hepatitis C virus (HCV) structural proteins under the elongation factor 1-${\alpha}$ promoter elicits HCV-specific cytotoxic T-lymphocytes (CTL). Vaccine, 18, 675-80.
  43. O'Hagan DT, Singh M, Dong C, et al (2004). Cationic microparticles are a potent delivery system for a HCV DNA vaccine. Vaccine, 23, 672-80.
  44. Palomares-Jerez MF, Nemesio H,Villalain J (2012). Interaction with membranes of the full C-terminal domain of protein NS4B from Hepatitis C virus. Biochim Biophys Acta, 63, 65-9.
  45. Palomares LA, Mena JA, Ramirez OT (2012). Simultaneous expression of recombinant proteins in the insect cell-baculovirus system: Production of virus-like particles. Methods, 56, 389-95.
  46. Pan Y, Wei W, Kang L, et al (2007). NS5A protein of HCV enhances HBV replication and resistance to interferon response. Biochemical and Biophysical Res Communications, 359, 70-5.
  47. Papa S, Rinaldi M, Mangia A, et al (1998). Development of a multigenic plasmid vector for HCV DNA immunization. Res in Virology, 149, 315-9.
  48. Park S-H, Lee SR, Hyun BH, et al (2008). Codelivery of PEGIFN-${\alpha}$ inhibits HCV DNA vaccine-induced T cell responses but not humoral responses in African green monkeys. Vaccine, 26, 3978-83.
  49. Patil A, Khanna N (2012). Novel membrane extraction procedure for the purification of hepatitis B surface antigen from Pichia pastoris. J Chromatography B, 898, 7-14.
  50. Piver E, Roingeard P,Pages J-C (2010). The cell biology of hepatitis C virus (HCV) lipid addiction: Molecular mechanisms and its potential importance in the clinic. Int J Biochemistry and amp; Cell Biology, 42, 869-79.
  51. Poranen MM,Tuma R (2004). Self-assembly of double-stranded RNA bacteriophages. Virus Res, 101, 93-100.
  52. Pratt JK, Donner P, McDaniel KF, et al (2005). Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-benzothiadiazines. Bioorganic and amp; Med Chemistry Letters, 15, 1577-82.
  53. Qiao M, Murata K, Davis AR, et al (2003). Hepatitis C virus-like particles combined with novel adjuvant systems enhance virusspecific immune responses. Hepatology, 37, 52-9.
  54. Quesnel-Vallieres M, Lemay M, Lapointe N, et al (2008). HCV quasispecies evolution during treatment with interferon alfa-2b and ribavirin in two children coinfected with HCV and HIV-1. J Clinical Virology, 43, 236-40.
  55. Radaelli A, Bonduelle O, Beggio P, et al (2007). Prime-boost immunization with DNA, recombinant fowlpox virus and VLPSHIV elicit both neutralizing antibodies and $IFN{\gamma}$-producing T cells against the HIV-envelope protein in mice that control env-bearing tumour cells. Vaccine, 25, 2128-38.
  56. Roffi L, Ricci A, Ogliari C, et al (1998). HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients. J Hepatology, 29, 701-6.
  57. Ma X, Forns X, Gutierrez R, et al (2002). DNA-based vaccination against hepatitis C virus (HCV): effect of expressing different forms of HCV E2 protein and use of CpG-optimized vectors in mice. Vaccine, 20, 3263-71.
  58. Ma Y, Yates J, Liang Y, et al (2008). NS3 helicase domains involved in infectious intracellular hepatitis C virus particle assembly. J Virol, 82, 7624-39.
  59. Mangia A, Cascavilla I, Lezzi G, et al (1997). HCV genotypes in patients with liver disease of different stages and severity. J Hepatology, 26, 1173-8.
  60. Masalova OV, Atanadze SN, Samokhvalov EI, et al (1998). Detection of hepatitis C virus core protein circulating within different virus particle populations. J Med Virol, 55, 1-6.<1::AID-JMV1>3.0.CO;2-7
  61. Matsuo E, Tani H, Lim CK, et al (2006). Characterization of HCVlike particles produced in a human hepatoma cell line by a recombinant baculovirus. Biochemical and Biophysical Res Communications, 340, 200-8.
  62. Matsuura Y, Tani H, Suzuki K, et al (2001). Characterization of Pseudotype VSV Possessing HCV Envelope Proteins. Virology, 286, 263-75.
  63. Mavromara P, Sall A, Kalinina O, et al (2005). The impact of HCV diversity on diagnosis tools for HCV infection. Medecine et Maladies Infectieuses, 35, 103-4.
  64. Memarnejadian A, Roohvand F (2010). Fusion of HBsAg and prime/ boosting augment Th1 and CTL responses to HCV polytope DNA vaccine. Cellular Immunology, 261, 93-8.
  65. Mihailova M, Boos M, Petrovskis I, et al (2006). Recombinant viruslike particles as a carrier of B- and T-cell epitopes of hepatitis C virus (HCV). Vaccine, 24, 4369-77.
  66. Mizui M-a, Moriya T, Sasaki F, et al (1994). Relation between HCV genotypes and the prevalence of antibodies against 5-1-1 and C100-3 in Japanese blood donors seropositive for hepatitis C virus. Int Hepatology Communications, 2, 183-5.
  67. Mizukoshi F, Yamamoto T, Mitsuki Y-Y, et al (2009). Activation of HIV-1 Gag-specific CD8+ T cells by yeast-derived VLP-pulsed dendritic cells is influenced by the level of mannose on the VLP antigen. Microbes and Infection, 11, 191-7.
  68. Mukherjee S, Thorsteinsson MV, Johnston LB, et al (2008). A quantitative description of in vitro assembly of human papillomavirus 16 virus-like particles. J Molecular Biology, 381, 229-37.
  69. Nakabayashi J (2012). A compartmentalization model of hepatitis C virus replication: An appropriate distribution of HCV RNA for the effective replication. J Theoretical Biology, 300, 110-7.
  70. Newcomb WW, Homa FL, Thomsen DR, et al (2001). In Vitro assembly of the herpes simplex virus procapsid: formation of small procapsids at reduced scaffolding protein concentration. J Structural Biology, 133, 23-31.
  71. Nguyen H, Sankaran S, Dandekar S (2006). Hepatitis C virus core protein induces expression of genes regulating immune evasion and anti-apoptosis in hepatocytes. Virology, 354, 58-68.
  72. Koev G, Dekhtyar T, Han L, et al (2007). Antiviral interactions of an HCV polymerase inhibitor with an HCV protease inhibitor or interferon in vitro. Antiviral Res, 73, 78-83.
  73. Korba B, Abigail M, Marc A, et al (2007). Nitazoxanide is an effective antiviral agent against both HBV and HCV replication in vitro. Antiviral Res, 74, 40-3.
  74. Kouvatsis V, Argnani R, Tsitoura E, et al (2007). Characterization of herpes simplex virus type 1 recombinants that express and incorporate high levels of HCV E2-gC chimeric proteins. Virus Research, 123, 40-9.
  75. Krishnadas DK, Li W, Kumar R, et al (2010). HCV-core and NS3 antigens play disparate role in inducing regulatory or effector T cells in vivo: Implications for viral persistence or clearance. Vaccine, 28, 2104-14.
  76. Lai C-W, Chan Z-R, Yang D-G, et al (2006). Accelerated induction of apoptosis in insect cells by baculovirus-expressed SARS-CoV membrane protein. FEBS Letters, 580, 3829-34.
  77. Lal SK, Tulasiram P, Jameel S (1997). Expression and characterization of the hepatitis E virus ORF3 protein in the methylotrophic yeast, Pichia pastoris. Gene, 190, 63-7.
  78. Lawitz E, Godofsky E, Rouzier R, et al (2011). Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. Antiviral Res, 89, 238-45.
  79. Lee MS, Lebeda FJ,Olson MA (2009). Fold prediction of VP24 protein of Ebola and Marburg viruses using de novo fragment assembly. J Structural Biology, 167, 136-44.
  80. Lee S, Kim YS, Jo M, et al (2007). Chip-based detection of hepatitis C virus using RNA aptamers that specifically bind to HCV core antigen. Biochemical and Biophysical Res Communications, 358, 47-52.
  81. Lenhard T, Maul G, Haase W, et al (1996). A new set of versatile vectors for the heterologous expression of foreign genes using the baculovirus system. Gene, 169, 187-90.
  82. Liu F, Ge S, Li L, et al (2012). Virus-like particles: potential veterinary vaccine immunogens. Res Veterinary Sci, 93, 553-9.
  83. Liu H, Wang D,Yang X (2012). Preparation of polymerisation raspberry-like core-corona composite via heterocoagulated self-assembly based on hydrogen-bonding interaction. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 397, 48-58.
  84. Lorenzo L J, Duenas-Carrera S, Falcon V, et al (2001). Assembly of truncated HCV core antigen into virus-like particles in escherichia coli. Biochemical and Biophysical Res Communications, 281, 962-5.
  85. Lunsdorf H, Gurramkonda C, Adnan A, et al (2011). Virus-like particle production with yeast: ultrastructural and immunocytochemical insights into Pichia pastoris producing high levels of the hepatitis B surface antigen. Microb Cell Fact, 10, 48-53.
  86. Ide T, Kumashiro R, Hino T, et al (2002). Short term and two-step interferon therapy for chronic hepatitis C patients with low HCV RNA levels. Hepatology Res, 22, 145-51.
  87. Idobe-Fujii Y, Ogi N, Hosho K, et al (2006). Hepatocellular carcinoma with sarcomatous change arising after eradication of HCV via interferon therapy. Clinical Imaging, 30, 416-9.
  88. Ikejiri M, Ohshima T, Kato K, et al (2007). 5'-O-Masked 2'-deoxyadenosine analogues as lead compounds for hepatitis C virus (HCV) therapeutic agents. Bioorganic and amp; Medicinal Chemistry, 15, 6882-92.
  89. Iken K, Huang L, Bekele H, et al (2006). Apoptosis of activated CD4+ and CD8+ T cells is enhanced by co-culture with hepatocytes expressing hepatitis C virus (HCV) structural proteins through FasL induction. Virology, 346, 363-72.
  90. Ivanova L, Le L, Schlesinger MJ (1995). Characterization of revertants of a Sindbis virus 6K gene mutant that affects proteolytic processing and virus assembly. Virus Res, 39, 165-79.
  91. Januszkiewicz-Lewandowska D, Wysocki J, Rembowska J, et al (2003). Transmission of HCV infection among long-term hospitalized onco-haematological patients. J Hospital Infection, 53, 120-3.
  92. Jorgensen CM, Lewis CA, Liu J (2012). An analysis of hepatitis C virus-related public inquiries from health professionals: 2009- 2010. Clin Infect Dis, 55, 54-7.
  93. Jouan L, Melancon P, Rodrigue-Gervais I, et al. (2010). Distinct antiviral signaling pathways in primary human hepatocytes and their differential disruption by HCV NS3 protease. J Hepatology, 52, 167-75.
  94. Kamili S, Drobeniuc J, Araujo AC, et al (2012). Laboratory diagnostics for hepatitis C virus infection. Clin Infect Dis, 55, 43-8.
  95. Kanto T, Hayashi N, Takehara T, et al (1995). Serial density analysis of hepatitis C virus particle populations in chronic hepatitis C patients treated with interferon-alpha. J Med Virol, 46, 230-7.
  96. Katsarou K, Serti E, Tsitoura P, et al (2009). Green fluorescent protein - Tagged HCV non-enveloped capsid like particles: Development of a new tool for tracking HCV core uptake. Biochimie, 91, 903-15.
  97. Kim H, Mazumdar B, Bose SK, et al (2012). Hepatitis C Virus Mediated Inhibition of Cathepsin S Increases Invariant Chain Expression on Hepatocyte Cell Surface. J Virol, 36, 56-9.
  98. Kim KH, Hong SP, Kim K, et al (2007). HCV core protein induces hepatic lipid accumulation by activating SREBP1 and $PPAR{\gamma}$. Biochem and Biophysic Res Com, 355, 883-8.
  99. Klade CS, Schuller E, Boehm T, et al (2012). Sustained viral load reduction in treatment-naive HCV genotype 1 infected patients after therapeutic peptide vaccination. Vaccine, 30, 2943-50.
  100. Klevens RM, Hu DJ, Jiles R, et al (2012). Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis, 55, 3-9.
  101. Guo X, Zhao Z, Xie J, et al (2012). Prediction of response to pegylated-interferon- inverted question mark and ribavirin therapy in Chinese patients infected with different hepatitis C virus genotype. Virol J, 9, 123-5.
  102. Gupta G, Qin H, Song J (2012). Intrinsically Unstructured Domain 3 of Hepatitis C Virus NS5A Forms a "Fuzzy Complex" with VAPB-MSP Domain Which Carries ALS-Causing Mutations. PLoS One, 7, 39261-4.
  103. Haller AA, Lauer GM, King TH, et al (2007). Whole recombinant yeast-based immunotherapy induces potent T cell responses targeting HCV NS3 and Core proteins. Vaccine, 25, 1452-63.
  104. Hamdy S, Haddadi A, Hung RW, Lavasanifar A (2011). Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations. Advanced Drug Delivery Reviews, 63, 943-55.
  105. Hanumantha RN, Baji BP, Rajendra L, et al (2011). Expression of codon optimized major capsid protein (L1) of human papillomavirus type 16 and 18 in Pichia pastoris; purification and characterization of the virus-like particles. Vaccine, 29, 7326-34.
  106. Harris SJ, Woodrow SA, Gearing AJH, et al (1996). The effects of adjuvants on CTL induction by V3:Ty-virus-like particles (V3- VLPs) in mice. Vaccine, 14, 971-6.
  107. Hechtfischer A, Meier-Ewert H, Marschall M (1999). A persistent variant of influenza C virus fails to interact with actin filaments during viral assembly. Virus Res, 61, 113-24.
  108. Honda A, Hatano M, Kohara M, et al (2000). HCV-core protein accelerates recovery from the insensitivity of liver cells to Fasmediated apoptosis induced by an injection of anti-Fas antibody in mice. J Hepatology, 33, 440-7.
  109. Hourioux C, Ait-Goughoulte M, Patient R, et al (2007). Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic reticulum membrane. Cell Microbiol, 9, 1014-27.
  110. Hsieh MJ, Lan KP, Liu HY, et al (2012). Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3ss signaling in hepatocytes. BMC Gastroenterol, 12, 74.
  111. Huang YJ, Kobayashi J,Yoshimura T (2002). Genome mapping and gene analysis of Antheraea pernyi nucleopolyhedrovirus for improvement of baculovirus expression vector system. J Bioscience and Bioengineering, 93, 183-91.
  112. Huang Z-S, Wang C-C, Wu H-N (2010). HCV NS3 protein helicase domain assists RNA structure conversion. FEBS Letters, 584, 2356-62.
  113. Huet C, Dabis F (2000). Transmission intra-familiale du virus de l'hepatite C dans le contexte de l'infection par le virus de l'immunodeficience humaine: actualites et implications pour le depistage. Medecine et Maladies Infectieuses, 30, 769-72.
  114. Huret C, Desjardins D, Miyalou M, et al (2012). Recombinant retrovirus-derived virus-like particle-based vaccines induce hepatitis C virus-specific cellular and neutralizing immune responses in mice. Vaccine, 25, 156-9.
  115. Falcon V, Acosta-Rivero N, Chinea G, et al (2003). Nuclear localization of nucleocapsid-like particles and HCV core protein in hepatocytes of a chronically HCV-infected patient. Biochemical and Biophysical Res Communications, 310, 54-8.
  116. Falcon V, Garcia C, Rosa M, et al (1999). Ultrastructural and immunocytochemical evidences of core-particle formation in the methylotrophicPichia pastorisyeast when expressing HCV structural proteins (core-E1). Tissue and Cell, 31, 117-25.
  117. Fane BA, Prevelige Jr PE (2003). Mechanism Of Scaffolding- Assisted Viral Assembly. In C Wah and E J John (Eds.). Advances in Protein Chemistry, 64, 259-99.
  118. Feinstone SM, Hu DJ,Major ME (2012). Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. Clin Infect Dis, 55, 25-32.
  119. Firbas C, Boehm T, Buerger V, et al (2010). Immunogenicity and safety of different injection routes and schedules of IC41, a Hepatitis C virus (HCV) peptide vaccine. Vaccine, 28, 2397-407.
  120. Firbas C, Jilma B, Tauber E, et al (2006). Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: A randomized, placebo controlled trial for dose optimization in 128 healthy subjects. Vaccine, 24, 4343-53.
  121. Fouad SA, Esmat S, Omran D, et al (2012). Noninvasive assessment of hepatic fibrosis in Egyptian patients with chronic hepatitis C virus infection. World J Gastroenterol, 18, 2988-994.
  122. Frey SE, Houghton M, Coates S, et al (2010). Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults. Vaccine, 28, 6367-73.
  123. Fujiwara K, Allison RD, Wang RY, et al (2012). Investigation of residual hepatitis C virus in presumed recovered subjects. Hepatology, 46, 31-42.
  124. Furusyo N, Ogawa E, Sudoh M, et al (2012). Raloxifene hydrochloride as a novel antiviral agent: inhibition of hepatitis C virus (HCV) replication. J Hepatology, 56, 438-40.
  125. Futatsumori-Sugai M, Tsumoto K (2010). Signal peptide design for improving recombinant protein secretion in the baculovirus expression vector system. Biochemical and Biophysical Res Communications, 391, 931-5.
  126. Gal-Tanamy M, Walker C, Foung S, et al (2009). Chapter 24 - Hepatitis C. In D T B Alan and R S Lawrence (Eds.), Vaccines for biodefense and emerging and neglected diseases. London: Academic Press. 413-440.
  127. Gelberg L, Robertson MJ, Arangua L, et al (2012). Prevalence, distribution, and correlates of hepatitis C virus infection among homeless adults in los angeles. Public Health Rep, 127, 407-21.
  128. Goldmann C, Stolte N, Nisslein T, et al (2000). Packaging of small molecules into VP1-virus-like particles of the human polyomavirus JC virus. J Virological Methods, 90, 85-90.
  129. Gunson RN, Shouval D, Roggendorf M, et al (2003). Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients. J Clinical Virology, 27, 213-30.
  130. Comanor L, Elkin C, Leung K, et al (2003). Successful HCV genotyping of previously failed and low viral load specimens using an HCV RNA qualitative assay based on transcriptionmediated amplification in conjunction with the line probe assay. J Clinical Virology, 28, 14-26.
  131. Coppola N, Pisapia R, Tonziello G, et al (2009). Improvement in the aetiological diagnosis of acute hepatitis C: A diagnostic protocol based on the anti-HCV-IgM titre and IgG Avidity Index. J Clinical Virology, 46, 222-9.
  132. Counihan NA, Rawlinson SM, Lindenbach BD (2011). Trafficking of hepatitis C virus core protein during virus particle assembly. PLoS Pathog, 7, 10-30.
  133. de Vicente J, Hendricks RT, Smith DB, et al (2009). Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones. Bioorganic and amp. Med Chemistry Letters, 19, 3642-6.
  134. de Witte L, Zoughlami Y, Aengeneyndt B, et al (2008). Binding of human papilloma virus L1 virus-like particles to dendritic cells is mediated through heparan sulfates and induces immune activation. Immunobiology, 212, 679-91.
  135. Delamare C, Carbonne B, Heim N, et al (1999). Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study. J Hepatology, 31, 416-20.
  136. Delgui L, Ona A, Gutierrez S, et al (2009). The capsid protein of infectious bursal disease virus contains a functional ${\alpha}4{\beta}1$ integrin ligand motif. Virology, 386, 360-72.
  137. Desjardins D, Huret C, Dalba C, et al (2009). Recombinant retroviruslike particle forming DNA vaccines in prime-boost immunization and their use for hepatitis C virus vaccine development. J Gene Med, 11, 313-25.
  138. Dreux M, Peitschmann T, Granier C, et al (2006). O.171 HDL inhibits HCV neutralisation by CD81-NOB antibodies by stimulating cell entry through activation of the scavenger receptor BI. J Clinical Virology, 36, 52-3.
  139. Duan H, Struble E, Zhong L, et al (2010). Hepatitis C virus with a naturally occurring single amino-acid substitution in the E2 envelope protein escapes neutralization by naturally-induced and vaccine-induced antibodies. Vaccine, 28, 4138-44.
  140. Dummer LA, Conceicao FR, Nizoli LQ, et al (2009). Cloning and expression of a truncated form of envelope glycoprotein D of Bovine herpesvirus type 5 in methylotrophic yeast Pichia pastoris. J Virological Methods, 161, 84-90.
  141. Eisenbach C, Freyse A, Lupu CM, et al (2006). Multigenotype HCVNS3 recombinant vaccinia viruses as a model for evaluation of cross-genotype immunity induced by HCV vaccines in the mouse. Vaccine, 24, 5140-8.
  142. Erensoy S (2001). Diagnosis of hepatitis C virus (HCV) infection and laboratory monitoring of its therapy. J Clinical Virology, 21, 271-81.
  143. Eskander EF, Abd-Rabou AA, Yahya SMM, et al (2012). Does interferon and ribavirin combination therapy ameliorate growth hormone deficiency in HCV genotype-4 infected patients? Clinical Biochemistry, 45, 3-6.
  144. Bossi V, Galli C (2004). Quantitative signal of anti-HCV by an automated assay predicts viremia in a population at high prevalence of hepatitis C virus infection. J Clinical Virology, 30, 45-9.
  145. Bourne P, Murray-Rust J, Lakey JH (2001). Protein-nucleic acid interactions: Folding and binding. Current Opinion in Structural Biology, 11, 9-10.
  146. Buckwold VE, Wei J, Huang Z, et al (2007). Antiviral activity of CHO-SS cell-derived human omega interferon and other human interferons against HCV RNA replicons and related viruses. Antiviral Res, 73, 118-25.
  147. Buonaguro L, Devito C, Tornesello ML, et al (2007). DNA-VLP prime-boost intra-nasal immunization induces cellular and humoral anti-HIV-1 systemic and mucosal immunity with crossclade neutralizing activity. Vaccine, 25, 5968-77.
  148. Cao C, Shi C, Li P, et al (1996). Diagnosis of hepatitis C Virus (HCV) infection by antigen-capturing ELISA. Clinical and Diagnostic Virology, 6, 137-45.
  149. Carreno V, Bartolome J, Castillo I, et al (2012). New perspectives in occult hepatitis C virus infection. World J Gastroenterol, 18, 2887-94.
  150. Carrion JA, Martinez-Bauer E, Crespo G, et al (2009). Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: A retrospective study. J Hepatology, 50, 719-28.
  151. Chase R, Skelton A, Xia E, et al (2009). A novel HCV NS3 protease mutation selected by combination treatment of the protease inhibitor boceprevir and NS5B polymerase inhibitors. Antiviral Res, 84, 178-84.
  152. Chatel-Chaix L, Melancon P, Racine ME, et al (2011). Y-box-binding protein 1 interacts with hepatitis C virus NS3/4A and influences the equilibrium between viral RNA replication and infectious particle production. J Virol, 85, 11022-37.
  153. Chen P-L, Wang M, Ou W-C, et al (2001). Disulfide bonds stabilize JC virus capsid-like structure by protecting calcium ions from chelation. FEBS Letters, 500, 109-13.
  154. Chen YL, Zacharias J, Vince R, et al (2012). C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus. Bioorg Med Chem, 35, 110-4.
  155. Chin R, Earnest-Silveira L, Koeberlein B, et al (2008). Recombinant HCV virus like particles to induce humoral and nutralising antibody response to HCV. J Hepatology, 48, 235-7.
  156. Ciccaglione AR, Marcantonio C, Equestre M, et al (1998). Secretion and purification of HCV E1 protein forms as glutathione-Stransferase fusion in the baculovirus insect cell system. Virus Res, 55, 157-65.
  157. Ciotti M, Marcuccilli F, Guenci T, et al (2010). A multicenter evaluation of the Abbott RealTime HCV Genotype II assay. J Virological Methods, 167, 205-7.
  158. Clarysse C, Van den EC, Nevens F, et al (1995). Genotype, serum level of HCV-RNA and response to interferon-${\alpha}$ treatment in patients with chronic hepatitis C. Netherlands J Med, 47, 265-71.
  159. Ampurdanes S, Olmedo E, Maluenda MD, et al (1996). Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum. J Hepatology, 25, 827-32.
  160. Arase Y, Ikeda K, Chayama K, et al (2001). Efficacy of IFN therapy based on duration period of negative HCV-RNA during IFN administration. Hepatology Res, 19, 22-30.
  161. Attoui H, Maan S, Anthony SJ, Mertens P (2009). Chapter 3 - Bluetongue virus, other orbiviruses and other reoviruses: Their relationships and taxonomy Bluetongue. London: Academic Press, 23-52
  162. Ault KA, Giuliano AR, Edwards RP, et al (2004). A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine, 22, 3004-7.
  163. Balamurugan V, Renji R, Saha SN, et al (2003). Protective immune response of the capsid precursor polypeptide (P1) of foot and mouth disease virus type 'O' produced in Pichia pastoris. Virus Res, 92, 141-9.
  164. Barman S, Ali A, Hui EKW, et al (2001). Transport of viral proteins to the apical membranes and interaction of matrix protein with glycoproteins in the assembly of influenza viruses. Virus Res, 77, 61-9.
  165. Bassyouni I, Bassyouni R, Ibrahim N, et al (2012). elevated serum osteopontin levels in chronic hepatitis C virus infection: association with autoimmune rheumatologic manifestations. J Clin Immunol, 36,36-8
  166. Baumert TF, Vergalla J, Satoi J, et al (1999). Hepatitis C viruslike particles synthesized in insect cells as a potential vaccine candidate. Gastroenterology, 117, 1397-407.
  167. Bellamy AR, Both GW (1990). Molecular biology of rotaviruses. In F a M Karl Maramorosch and S Aaron J (Eds.). Advances in Virus Res, 38, 1-43.
  168. Belyaev AS, Hails RS, Roy P (1995). High-level expression of five foreign genes by a single recombinant baculovirus. Gene, 156, 229-33.
  169. Bevilacqua E, Fabris A, Floreano P, et al (2009). Genetic factors in mother-to-child transmission of HCV infection. Virology, 390, 64-70.
  170. Bhatti FA, Amin M, Saleem M (1995). Prevalence of antibody to hepatitis C virus in Pakistani thalassaemics by particle agglutination test utilizing C 200 and C 22-3 viral antigen coated particles. J Pak Med Assoc, 45, 269-71.
  171. Blanchard E, Brand D, Roingeard P (2003). Endogenous virus and hepatitis C virus-like particle budding in BHK-21 cells. J Virol, 77, 3888-9.
  172. Blanchard E, Brand D, Trassard S, et al (2002). Hepatitis C virus-like particle morphogenesis. J Virol, 76, 4073-9.
  173. Blazevic V, Lappalainen S, Nurminen K, et al (2011). Norovirus VLPs and rotavirus VP6 protein as combined vaccine for childhood gastroenteritis. Vaccine, 29, 8126-33.
  174. Blutt SE, Warfield KL, O'Neal CM, et al (2006). Host, viral, and vaccine factors that determine protective efficacy induced by rotavirus and virus-like particles (VLPs). Vaccine, 24, 1170-9.
  175. Abacioglu Y H, Davidson F, Simmonds P (1996). Sequence analysis of the 5' non coding region of Turkish HCV isolates: implications for PCR diagnosis. Clinical and Diagnostic Virology, 5, 211-4.
  176. Acosta-Rivero N, Aguilar JC, Musacchio A, et al (2001). characterization of the HCV Core virus-like particles produced in the methylotrophic yeast pichia pastoris. Biochemical and Biophysical Res Communications, 287, 122-5.
  177. Acosta-Rivero N, Alvarez-Obregon JC, Musacchio A, et al (2002). in vitro self-assembled HCV core virus-like particles induce a strong antibody immune response in sheep. Biochemical and Biophysical Res Communications, 290, 300-4.
  178. Acosta-Rivero N, Falcon V, Alvarez C, et al (2003). Structured HCV nucleocapsids composed of P21 core protein assemble primary in the nucleus of Pichia pastoris yeast. Biochemical and Biophysical Res Communications, 310, 48-53.
  179. Acosta-Rivero N, Rodriguez A, Musacchio A, et al (2004). In vitro assembly into virus-like particles is an intrinsic quality of Pichia pastoris derived HCV core protein. Biochemical and Biophysical Res Communications, 325, 68-74.
  180. Affranchino JL, Gonzalez SA (2010). In vitro assembly of the feline immunodeficiency virus Gag polyprotein. Virus Res, 150, 153-7.
  181. Ait-Goughoulte M, Hourioux C, Patient R, et al (2006). Core protein cleavage by signal peptide peptidase is required for hepatitis C virus-like particle assembly. J Gen Virol, 87, 855-60.
  182. Akazawa D, Morikawa K, Omi N, et al (2011). Production and characterization of HCV particles from serum-free culture. Vaccine, 29, 4821-8.
  183. Al Swaff R (2012). Correlation between alanine aminotransferase level, HCV-RNA titer and fibrosis stage in chronic HCV genotype 4 infection. Egyptian J Med Human Genetics, 13, 207-12.
  184. Albertoni G, Arnoni C P, Araujo PRB, et al (2010). Signal to cut-off (S/CO) ratio and detection of HCV genotype 1 by real-time PCR one-step method: is there any direct relationship? The Brazilian J Infectious Diseases, 14, 147-52.
  185. Alter G, Jost S, Rihn S, et al (2011). Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance. J Hepatology, 55, 278-88.
  186. Alvarez-Obregon JC, Duenas-Carrera S, Valenzuela C, et al (2001). A truncated HCV core protein elicits a potent immune response with a strong participation of cellular immunity components in mice. Vaccine, 19, 3940-6.

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