Antiviral Agents for Hepatitis Viruses

  • Robert K. Hamatake
  • Zhi Hong
  • Johnson Y. N. Lau
  • Weidong Zhong


HAV is a positive-sense single-stranded RNA virus belonging to the genus hepatovirus of the Picornaviridae family (1, 2). HAV infection occurs worldwide through the fecal-oral route and is an important cause of acute viral hepatitis, particularly in many developing countries. Although most patients recover completely from this disease, elderly patients have a substantial high mortality risk. Fulminant hepatitis is a rare complication of acute HAV infection (3). Superinfection by HAV in patients with preexisting liver diseases is often associated with more severe liver disease and increased morbidity and mortality (1).


Chronic Hepatitis Bovine Viral Diarrhea Virus Adefovir Dipivoxil Woodchuck Hepatitis Virus Duck Hepatitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Lemon S.M. Type A viral hepatitis: new development in an old disease. N Engl J Med 1985;313:1059–1067.PubMedCrossRefGoogle Scholar
  2. 2.
    Lemon S.M., Robertson B.H. Current perspectives in the virology and molecular biology of hepatitis A virus. Semin Virol 1993; 4:285–295.CrossRefGoogle Scholar
  3. 3.
    Ozsoyen S., Kocak N. Acute hepatic failure related to hepatitis A. Lancet 1989; 1:901.Google Scholar
  4. 4.
    Lemon S.M., Thomas D.L. Vaccines to prevent viral hepatitis. N Eng J Med 1997; 336:196–204.CrossRefGoogle Scholar
  5. 5.
    Innis B.L., Snitbhan R., Kunasol P. Protection against hepatitis A by an inactivated vaccine. JAMA 1994; 271:1328–1334.PubMedCrossRefGoogle Scholar
  6. 6.
    Werzberger A., Mensch B., Kuter B. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med 1992; 327:453–457.PubMedCrossRefGoogle Scholar
  7. 7.
    Sanchez F.S., Sosa I.R.G., Vargas G.M. Treatment of type A hepatitis with ribavirin. Clinical Applications of Ribavirin. Academic Press, Inc., 1984.Google Scholar
  8. 8.
    Hoofhagle J.H., Di Bisceglie A.M. Treatment of chronic viral hepatitis. N Engl J Med 1997; 336:347–356.CrossRefGoogle Scholar
  9. 9.
    Wong D.K.H., Cheung A.M., O’Rourke K., Naylor CD., Detsky A.S., Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis. Ann Intern Med 1993; 119:312–323.PubMedGoogle Scholar
  10. 10.
    Perrillo R.P., Rogenstein F.G., Peters M.G., DeSchryver-Kecskemeti K., Bodicky C.J., Campbell C.R., Kuhns M.C. Prednisone withdrawal followed by a recombinant alpha interferon in the treatment of chronic type B hepatitis. A randomized, controlled trial. Ann Intern Med 1988; 109:95–100.PubMedGoogle Scholar
  11. 11.
    Severini A., Liu X.Y., Wilson J.S., Tyrrell D.L.J. Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-b-L-2′,3′,-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother 1995; 39:1430–1435.PubMedCrossRefGoogle Scholar
  12. 12.
    Lai C.L., Chien R.N., Leung N.W.Y., Chang T.T., Guan R., Tai D.I., Ng K.Y., Wu P.C., Dent J.C., Barber J., Stephenson S.L., Gray D.F., Group A.H.L.S. A one-year trial of lamivudine for chronic hepatitis B. N Eng J Med 1998; 339:61–68.CrossRefGoogle Scholar
  13. 13.
    Dienstag J.L., Schiff E.R., Mitchell M., Casey D.E.J., Gitlin N., Lissoos T., Gleb L.D., Condreay L., Crowther L., Rubin M., Brown N. Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy. Hepatology 1999; 30:1082–1087.PubMedCrossRefGoogle Scholar
  14. 14.
    Liaw Y.F., Leung N.W., Chang T.T., Guan R., Tai D.I., Ng K.Y., Chien R.N., Dent J., Roman L., Edmundson S., Lai C.L. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology 2000; 119:172–180.PubMedCrossRefGoogle Scholar
  15. 15.
    Tassopoulos N.C., Volpes R., Pastore G., Heathcote J., Buti M., Goldin R.D., Hawley S., Barber J., Condreay L., Gray D.F. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 1999; 29:889–896.PubMedCrossRefGoogle Scholar
  16. 16.
    Villeneuve J.-P., Condreay L.D., Willems B., Pomier-Layrargues G., Fenyves D., Bilodeau M., Leduc R., Peltekian K., Wong F., Margulies M., Heathcote E.J. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 2000; 31:207–210.PubMedCrossRefGoogle Scholar
  17. 17.
    Dienstag J.L., Perrillo R.P., Schiff E.R., Bartholomew M., Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995; 333:1657–1661.PubMedCrossRefGoogle Scholar
  18. 18.
    Nevens F., Main J., Honkoop P., Tyrrell D.L., Barber J., Sullivan M.T., Fevery J., De Man R.A., Thomas H.C. Lamivudine therapy for chronic hepatitis B: a six-month randomized dose-ranging study. Gastroenterology 1997; 113:1258–1263.PubMedCrossRefGoogle Scholar
  19. 19.
    Tuttleman J.S., Pourcel C., Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 1986; 47:451–460.PubMedCrossRefGoogle Scholar
  20. 20.
    Civitico G.M., Locarnini S.A. The half-life of duck hepatitis B virus supercoiled DNA in congenitally infected primary hepatocyte cultures. Virology 1994; 203:81–89.PubMedCrossRefGoogle Scholar
  21. 21.
    Moraleda G., Saputelli J., Aldrich C.E., Averett D., Condreay L., Mason W.S. Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol 1997; 71:9392–9399.PubMedGoogle Scholar
  22. 22.
    Dandri M., Burda M.R., Will H., Petersen J. Increased hepatocyte turnover and inhibition of woodchuck hepatitis B virus replication by adefovir in vitro do not lead to reduction of the closed circular DNA. Hepatology 2000; 32:139–146.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu Y., Yamamoto T., Cullen J., Saputelli J., Aldrich C.E., Miller D.S., Litwin S., Furman P.A., Jilbert A.R., Mason W.S. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J Virol 2001; 75:311–322.PubMedCrossRefGoogle Scholar
  24. 24.
    Fischer K.P., Tyrell D.L.J. Generation of duck hepatitis B virus polymerase mutants through site-directed mutagenesis which demonstrate resistance to lamivudine ((-)-beta-L-2′,3′-dideoxy-3′-thiacytidine) in vitro. Antimicrob Agents Chemother 1996; 40:1957–1960.PubMedGoogle Scholar
  25. 25.
    Tipples G.A., Ma M.M., Fischer K.P., Bain V.G., Kneteman N.M., Tyrrell D.L.J. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 1996; 24:714–717.PubMedGoogle Scholar
  26. 26.
    Chang T.T., Lai C.L., Liaw Y.F., Guan R., Lim S.G., Lee CM., Ng K.Y., et al. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for four years [abstract]. Antiviral Therapy 2000; 5(Suppl 1):44.Google Scholar
  27. 27.
    Liaw Y.F., Chien R.N., Yeh C.T., Tsai S.L., Chu C.M. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology 1999; 30:567–572.PubMedCrossRefGoogle Scholar
  28. 28.
    Bartenschlager R., Junker-Niepmann M., Schaller H. The P-gene product of hepatitis B virus is required as a structural component for genomic RNA encapsidation. J Virol 1990; 64:5324–5332.PubMedGoogle Scholar
  29. 29.
    Hirsch R.C., Lavine J.E., Chang L.J., Varmus H.E., Ganem D. Polymerase gene products of hepatitis B viruses are required for genomic RNA packaging as well as for reverse transcription. Nature (London) 1990; 344:552–555.CrossRefGoogle Scholar
  30. 30.
    Nassal M., Rieger A. A bulged region of the hepatitis B virus RNA encapsidation signal contains the replication origin for discontinuous first-strand DNA synthesis. J Virol 1996; 70:2764–2773.PubMedGoogle Scholar
  31. 31.
    Tavis J.E., Perri S., Ganem D.E. Hepadnavirus reverse transcription initiates within the stem-loop of the RNA packaging signal and employs a novel strand transfer. J Virol 1994; 68:3536–3543.PubMedGoogle Scholar
  32. 32.
    Bartenschlager R., Junker-Niepmann M., Schaller H. The amino-terminal domain of the hepadnaviral P-gene encodes the terminal protein (genome-linked protein) believed to prime reverse transcription. EMBO J 1990; 11:4185–4192.Google Scholar
  33. 33.
    Wang G.H., Seeger C. The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell 1992; 71:663–670.PubMedCrossRefGoogle Scholar
  34. 34.
    Summers J., Mason W.S. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 1982; 29:403–415.PubMedCrossRefGoogle Scholar
  35. 35.
    Radziwill G., Tucker W., Schaller H. Mutational analysis of the hepatitis B virus P gene product: domain structure and Rnase H activity. J Virol 1990; 64:613–620.PubMedGoogle Scholar
  36. 36.
    Lanford R.E., Notvall L., Beames B. Nucleotide priming and reverse transcriptase activity of hepatitis B virus polymerase expressed in insect cells. J Virol 1995; 69:4431–4439.PubMedGoogle Scholar
  37. 37.
    Lee H.J., Kwon Y.T., Rho H.M., Jung G. Expression of hepatitis B virus polymerase gene in E. coli. Biotechnology Letters 1993; 15:821–826.Google Scholar
  38. 38.
    Seifer M., Hamatake R., Bifano M., Standring DN. Generation of replication-competent hepatitis B virus nucleocapsids in insect cells. J Virol 1998; 72:2765–2776.PubMedGoogle Scholar
  39. 39.
    Sells M.A., Chen M.L., Acs G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc Nal Acad Sci USA 1987; 84:1005–1009.CrossRefGoogle Scholar
  40. 40.
    Ladner S.K., Miller T.J., Otto M.J., King R.W. The M539V HBV polymerase variation responsible for 3TC-resistance also confers cross-resistance to other nucleoside analogs. Antivir Chem Chemother 1998; 9:65–72.PubMedGoogle Scholar
  41. 41.
    Fu L., Cheng Y.C. Characterization of novel human hepatoma cell lines with stable hepatitis B virus secretion for evaluating new compounds against lamivudine- and penciclovir-resistant virus. Antimicrob Agents Chemother 2000; 44:3402–3407.PubMedCrossRefGoogle Scholar
  42. 42.
    Korba B.E., Milman G. A cell culture assay for compounds which inhibit hepatitis B virus replication. Antivir Res 1991; 15:217–228.PubMedCrossRefGoogle Scholar
  43. 43.
    Ying C, De Clercq E., Nicholson W., Furman P., Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral Hepat 2000; 7:161–165.PubMedCrossRefGoogle Scholar
  44. 44.
    Perrillo R., Schiff E., Yoshida E., Statler A., Hirsch K., Wright T., Gutfreund K., Lamy P., Murray A. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000; 32:129–134.PubMedCrossRefGoogle Scholar
  45. 45.
    Doong S.L., Tsai C.H., Schinazi R.F., Liotta D.C., Cheng Y.C. Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues. Proc Natl Acad Sci USA 1991; 88:8495–8499.PubMedCrossRefGoogle Scholar
  46. 46.
    Korba B.E., Boyd M.R. Penciclovir is a selective inhibitor of hepatitis B virus replication in cultured human hepatoblastoma cells. Antimicrob Agents Chemother 1996; 40:1282–1284.PubMedGoogle Scholar
  47. 47.
    Innaimo S.F., Seifer M., Bisacchi G.S., Standring D.N., Zahler R., Colonno R.J. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother 1997; 41:1444–1448.PubMedGoogle Scholar
  48. 48.
    Furman P.A., Davis M., Liotta D.C., Paff M., Frick L.W., Nelson D.J., Dornsife R.E., Wurster J.A., Wilson L.J., Fyfe J.A. The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992;36:2686–2692.PubMedCrossRefGoogle Scholar
  49. 49.
    Heijtink R.A., De Wilde G.A., Kruining J., Berk L., Balzarini J., De Clerq E., Holy A., Schalm S.W. Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res 1993; 21:141–153.PubMedCrossRefGoogle Scholar
  50. 50.
    Chu C.K., Ma T., Shanmuganathan K., Wang C., Xiang Y., Pai S.B., Yao G.Q., Sommadossi J.P., Cheng Y.C. Use of 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus. Antimicrob Agents Chemother 1995; 39:979–981.PubMedCrossRefGoogle Scholar
  51. 51.
    Bryant M.L., Bridges E.G., Placidi L., Faraj A., Loi A.G., Pierra C., Dukhan D., Gosselin G., Imbach J.L., Hernandez B., Juodawlkis A., Tennant B., Korba B., Cote P., Marrion P., Cretton-Scott E., Schinazi R.F., Sommadossi J.P. Antiviral L-Nucleosides spécifie for hepatitis B virus infection. Antimicrob Agents Chemother 2001; 45:229–235.PubMedCrossRefGoogle Scholar
  52. 52.
    Xiong X., Flores C., Yang H., Toole J.J., Gibbs C.S. Mutations in hepatitis B polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 1999; 28:1669–1673.CrossRefGoogle Scholar
  53. 53.
    Fu L., Liu S.H., Cheng Y.C. Sensitivity of L-(-)2′,3′-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues. Biochem Pharmacol 1999; 55:1351–1359.CrossRefGoogle Scholar
  54. 54.
    Chang C., Enders G., Sprengel R., Peters N., Varmus H.E., Ganem D. Expression of the precore region of an avian hepatitis B virus is not required for viral replication. J Virol 1987;61:3322–3325.PubMedGoogle Scholar
  55. 55.
    Chen H.S., Kew M.C., Hornbuckle W.E., Tennant B.C., Cote P.J., Gerin J.L., Purcell R.H., Miller R.H. The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J Virol 1992; 66:5682–5684.PubMedGoogle Scholar
  56. 56.
    Milich D.R., Jones J.E., Hughes J.L., Price J., Raney A.K., McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in uterol? Proc Natl Acad Sci USA 1990; 87:6599–6603.PubMedCrossRefGoogle Scholar
  57. 57.
    Seifer M., Standring D.N. Assembly and antigenicity of hepatitis B virus core particles. Intervirology 1995; 38:47–62.PubMedGoogle Scholar
  58. 58.
    Nassal M. The arginine-rich domain of the hepatitis B virus core protein is required for pregenome encapsidation and productive viral positive-strand DNA synthesis but not for virus assembly. J Virol 1992; 66:4107–4116.PubMedGoogle Scholar
  59. 59.
    Kock J., Wieland S., Blum H.E., von Weizsacker F. Duck hepatitis B virus nucleocapsids formed by N-terminally extended or C-terminally truncated core proteins disintegrate during viral DNA maturation. J Virol 1998; 72:9116–9120.PubMedGoogle Scholar
  60. 60.
    Hatton T., Zhou S., Standring D.N. RNA- and DNA-binding activities in hepatitis B virus capsid protein: a model for their roles in viral replication. J Virol 1992; 66:5232–5241.PubMedGoogle Scholar
  61. 61.
    Pogam S.L., Yuan T.T., Sahu G.K., Chatterjee S., Shih C. Low-level secretion of human hepatitis B virus virions caused by two independent, naturally occurring mutations (P5T and L60V) in the capsid protein. J Virol 2000; 74:9099–9105.PubMedCrossRefGoogle Scholar
  62. 62.
    Yuan T.T., Sahu G.K., Whitehead W., Greenberg R., Shih C. The mechanism of an “immature secretion” phenotype of a highly frequent naturally occurring missense mutation at codon 97 of human hepatitis B virus core antigen. J Virol 1999; 73:5731–5740.PubMedGoogle Scholar
  63. 63.
    Liao W., Ou J.-H. Phosphorylation and nuclear localization of the hepatitis B virus core protein: significance of serine in the three repeated SPRRR motifs. J Virol 1995;69:1025–1029.PubMedGoogle Scholar
  64. 64.
    Scaglioni P.P., Melegari M., Wands J.R. Characterization of hepatitis B virus core mutants that inhibit viral replication. Virology 1994; 205:112–120.PubMedCrossRefGoogle Scholar
  65. 65.
    Dyson M.R., Murray K. Selection of peptide inhibitors of interactions involved in complex protein assemblies: Association of the core and surface antigens of hepatitis B virus. Proc Natl Acad Sci USA 1995; 92:2194–2198.PubMedCrossRefGoogle Scholar
  66. 66.
    Bottcher B., Tsuji N., Takahashi H., Dyson M.R., Zhao S., Crowther R.A., Murray K. Peptides that block hepatitis B virus assembly: analysis by cryomicroscopy, mutagenesis and transfection. EMBO J. 1998;17:6839–6845.PubMedCrossRefGoogle Scholar
  67. 67.
    King R.W., Ladner S.K., Miller T.J., Zaifert K., Perni R.B., Conway S.C., Otto J.J. Inhibition of human hepatitis B virus replication by AT-61, a phenylpropenamide derivative, alone and in combination with (-)β-L-2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother 1998; 42:3179–3186.PubMedGoogle Scholar
  68. 68.
    Heerman K.H., Gerlich W.H. “Surface proteins of hepatitis B viruses.” In Molecular Biology of the Hepatitis B virus, A. McLachlan, ed., Boca Raton, FL: CRC, pp 109–143. 1991.Google Scholar
  69. 69.
    Kuroki K., Eng F., Ishikawa T., Turck C., Harada F., Ganem D. gp180, a host cell glycoprotein that binds duck hepatitis B virus particles, is encoded by a member of the carboxypeptidase gene family. J Biol Chem 1995; 270:15022–15028.PubMedCrossRefGoogle Scholar
  70. 70.
    Tong S., Li, J., Wands J.R. Interaction between duck hepatitis B virus and a 170-kilodalton cellular protein is mediated through a neutralizing epitope of the pre-S region and occurs during viral infection. J Virol 1995; 69:7106–7112.PubMedGoogle Scholar
  71. 71.
    Tong S., Li J., Wands J.R. Carboxypeptidase D is an avian hepatitis B virus receptor. J Virol 1999; 73:8696–8702.PubMedGoogle Scholar
  72. 72.
    Urban S., Breiner K.M., Fehler F., Klingmuller U., Schaller H. Avian hepatitis B virus infection is initiated by the interaction of a distinct pre-S subdomain with the cellular receptor gp 180. J Virol 1998; 72:8089–8097.PubMedGoogle Scholar
  73. 73.
    Urban S., Schwarz C., Marx U.C., Zentgraf H., Schaller H., Multhaup G. Receptor recognition by a hepatitis B virus reveals a novel mode of high affinity virus-receptor interaction. EMBO J 2000; 19:1217–1227.PubMedCrossRefGoogle Scholar
  74. 74.
    Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di M.P., Marmon S., Sutton R.E., Hill C.M., Davis C.B., Peiper S.C., Schall T.J., Littman D.R., Landau N.R. Identification of a major co-receptor for primary isolates of HIV-1. Nature (London) 1996; 381:661–666.CrossRefGoogle Scholar
  75. 75.
    Feng Y., Broder C.C., Kennedy P.E., Berger E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272:872–877.PubMedCrossRefGoogle Scholar
  76. 76.
    Mehta A., Lu X., Block T.M., Blumberg B.S., Dwek R.A. Hepatitis B virus (HBV) envelope glycoproteins vary drastically in their sensitivity to glycan processing: Evidence that alteration of a single N-linked glycosylation site can regulate HBV secretion. Proc Natl Acad Sci USA 1997; 94:1822–1827.PubMedCrossRefGoogle Scholar
  77. 77.
    Block T.M., Lu X., Platt F.M., Foster G.R., Gerlich W.H., Blumberg B.S., Dwek R.A. Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin. Proc Natl Acad Sci USA 1994; 91:2235–2239.PubMedCrossRefGoogle Scholar
  78. 78.
    Block T.M., Lu X., Mehta A.S., Blumberg B.S., Tennant B., Ebling M., Korba B., Lansky D.M., Jacob G.S., Dwek R.A. Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking. Nature Med 1998; 4:610–614.PubMedCrossRefGoogle Scholar
  79. 79.
    Blum H.E., Zhang Z.S., Galun E., von Weizsacker F., Garner B., Liang T.J., Wands J.R. Hepatitis B virus X protein is not central to the viral life cycle in vitro. J Virol 1992; 66:1223–1227.PubMedGoogle Scholar
  80. 80.
    Yaginuma K., Shirakata Y., Kobayashi M., Koike K. Hepatitis B virus (HBV) particles are produced in a cell culture system by transient expression of transfected HBV DNA. Proc Natl Acad Sci USA 1987; 84:2678–2682.PubMedCrossRefGoogle Scholar
  81. 81.
    Zoulim F., Saputelli J., Seeger C. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol 1994; 68:2026–2030.PubMedGoogle Scholar
  82. 82.
    Chen H.S., Kaneko S., Girones R., Anderson R.W., Hornbuckle W.E., Tennant B.C., Cote P.J., Gerin J.L., Purcell R.H., Miller R.H. The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol 1993;67:1218–1226.PubMedGoogle Scholar
  83. 83.
    Chisari F.V., Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995; 13:29-60.PubMedCrossRefGoogle Scholar
  84. 84.
    Bertoletti A., Maini M.K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol 2000; 3:387–392.PubMedCrossRefGoogle Scholar
  85. 85.
    Bertoletti A., Ferrari C., Fiaccadori F., Penna A., Margolskee R., Schlicht H.J., Fowler P., Guilhot S., Chisari F.V. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci USA 1991; 88:10445–10449.PubMedCrossRefGoogle Scholar
  86. 86.
    Nayersina R., Fowler P., Guilhot S., Missale G., Cerny A., Schlicht H.J., Vitiello A., Chesnut R., Person J.L., Redeker A.G., et al. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol 1993; 150:4659–71.PubMedGoogle Scholar
  87. 87.
    Maini M.K., Boni C., Ogg G.S., King A.S., Reignat S., Lee C.K., Larrubia J.R., Webster G.J., McMichael A.J., Ferrari C., Williams R., Vergani D., Bertoletti A. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 1999; 117:1386–96.PubMedCrossRefGoogle Scholar
  88. 88.
    Rehermann B., Fowler P., Sidney J., Person J., Redeker A., Brown M., Moss B., Sette A., Chisari F.V. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med 1995; 181:1047–1058.PubMedCrossRefGoogle Scholar
  89. 89.
    Bertoletti A., Costanzo A., Chisari F.V., Levrero M., Artini M., Sette A., Penna A., Guiberti A., Fiaccadori F., Ferrari C. Cytotoxic T lymphocyte response to a wild-type hepatitis B virus carrying substitutions within the epitope. J Exp Med 1994; 180:933–943.PubMedCrossRefGoogle Scholar
  90. 90.
    Guidotti L.G., Ishikawa T., Hobbs M.V., Matzke B., Schreiber R., Chisari F.V. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 1996; 4:25–36.PubMedCrossRefGoogle Scholar
  91. 91.
    Guidotti L.G., Rochford R., Chung J., Shapiro M., Purcell R., Chisari F.V. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284:825–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Webster G.J., Reignat S., Maini M.K., Whalley S.A., Ogg G.S., King A., Brown D., Amlot P.L., Williams R., Vergani D., Dusheiko G.M., Bertoletti A. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32:1117–24.PubMedCrossRefGoogle Scholar
  93. 93.
    Biron C.A., Nguyen K.B., Pien G.C., Cousens L.P., Salazar-Mather T.P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Ann Rev Immunol 1999; 17:189–220.CrossRefGoogle Scholar
  94. 94.
    Guo J.T., Zhou H., Liu C., Aldrich C., Saputelli J., Whitaker T., Barrasa M.I., Mason W.S., Seeger C. Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections. J Virol 2000; 74:1495–1505.PubMedCrossRefGoogle Scholar
  95. 95.
    Kajino K., Jilbert A.R., Saputelli J., Aldrich C.E., Cullen J., Mason W.S. Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J Virol 1994; 68:5792–5803.PubMedGoogle Scholar
  96. 96.
    Livingston B.D., Crimi C., Grey H., Ishioka G., Chisari F.V., Fikes J., Grey H., Chesnut R.W., Sette A. The hepatitis B virus-specific CTL responses induced in humans by lipopeptide vaccination are comparable to those elicited by acute viral infection. J Immunol 1997; 159:1383–139.PubMedGoogle Scholar
  97. 97.
    Heathcote J., McHutchison J., Lee S., Tong M., Benner K., Minuk G., Wright T., Fikes J., Livingston B., Sette A., Chestnut R. A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. Hepatology 1999; 30:531–536.PubMedCrossRefGoogle Scholar
  98. 98.
    Pol S., Michel M.L., Brechot C. Immune therapy of hepatitis B virus chronic infection. Hepatology 2000; 31:548–549.PubMedCrossRefGoogle Scholar
  99. 99.
    Gurunathan S., Wu C.Y., Freidag B.L., Seder R.A. DNA vaccines: a key for inducing long-term cellular immunity. Curr Opin Immunol 2000; 12:442–447.PubMedCrossRefGoogle Scholar
  100. 100.
    Rollier C., Sunyach C., Barraud L., Madani N., Jamard C., Trepo C., Cova L. Protective and therapeutic effect of DNA-based immunization against hepadnavirus large envelope protein. Gastroenterology 1999; 116:658–665.PubMedCrossRefGoogle Scholar
  101. 101.
    Roy M.J., Wu M.S., Barr L.J., Fuller J.T., Tussey L.G., Speller S., Culp J., Burkholder J.K., Swain W.F., Dixon R.M., Widera G., Vessey R., King A., Ogg G., Gallimore A., Haynes J.R., Heydenburg F.D. Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine 2000; 19:764–778.PubMedCrossRefGoogle Scholar
  102. 102.
    Musch E., Hogemann B., Gerritzen A., Fischer H.P., Wiese M., Kruis W., Malek M., Gugler R., Schmidt G., Huchzermeyer H., Gerlach U., Dengler H.J., Sauerbruch T. Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B. Hepatogastroenterology 1998; 45:2282–2294.PubMedGoogle Scholar
  103. 103.
    Lau J.Y., Lai C.L., Wu P.C., Chung H.T., Lok A.S., Lin H.J. A randomised controlled trial of recombinant interferon-gamma in Chinese patients with chronic hepatitis B virus infection. J Med Virol 1991; 34:184–187.PubMedCrossRefGoogle Scholar
  104. 104.
    Cavanaugh V.J., Guidotti L.G., Chisari F.V. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. J Virol 1997; 71:3236–3243.PubMedGoogle Scholar
  105. 105.
    Carreno V., Zeuzem S., Hopf U., Marcellin P., Cooksley W.G., Fevery J., Diago M., Reddy R., Peters M., Rittweger K., Rakhit A., Pardo M. A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. J Hepatol 2000; 32:317–324.PubMedCrossRefGoogle Scholar
  106. 106.
    Schalm S.W., Heathcote J., Cianciara J., Farrell G., Sherman M., Willems B., Dhillon A., Moorat A., Barber J., Gray D.F. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000; 46:562–568.PubMedCrossRefGoogle Scholar
  107. 107.
    Boni C, Bertoletti A., Penna A., Cavalli A., Pilli M., Urbani S., Scognamiglio P., Boehme R., Panebianco R., Fiaccadori F., Ferrari C. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998; 102:968–975.PubMedCrossRefGoogle Scholar
  108. 108.
    Sidwell R.W., Huffman J.H., Khare G.P., Allen L.B., Witknowski J.T., Robins R.K. Broad-spectrum antiviral activity of Virazole: l-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 1972; 177:705–706.PubMedCrossRefGoogle Scholar
  109. 109.
    Tam R.C., Pai B., Bard J., Lim C., Averett D.R., Phau U.T., Milovanovic T. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol 1999; 30:376–382.PubMedCrossRefGoogle Scholar
  110. 110.
    Tarn R.C., Lim C., Bard J., Pai B. Contact hypersensitivity responses following ribavirin treatment in vivo are influenced by Type 1 cytokine polarization, regulation of IL-10 expression, and costimulatory signaling. J Immunol 1999; 163:3709–3717.Google Scholar
  111. 111.
    Hultgren C., Milich D.R., Weiland O., Sallberg M. The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol 1998; 79:2381–2391.PubMedGoogle Scholar
  112. 112.
    Korba B.E., Cote P., Hornbuckle W., Tennant B.C., Gerin J.L. Treatment of chronic woodchuck hepatitis virus infection in the eastern woodchuck (Marmota monax) with nucleoside analogues is predictive of therapy for chronic hepatitis B virus infection in humans. Hepatology 2000; 31:1165–1175.PubMedCrossRefGoogle Scholar
  113. 113.
    Markland W., McQuaid T.J., Jain J., Kwong A.D. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother 2000; 44:859–866.PubMedCrossRefGoogle Scholar
  114. 114.
    Fried M.W., Fong T.L., Swain M.G., Park Y., Beames M.P., Banks S.M., Hoofhagle J.H., Di Bisceglie A.M. Therapy of chronic hepatitis B with a 6-month course of ribavirin. J Hepatol 1994; 21:145-150.PubMedCrossRefGoogle Scholar
  115. 115.
    Kakumu S., Yoshioka K., Wakita T., Ishikawa T., Takayanagi M., Higashi Y. Pilot study of ribavirin and interferon-β for chronic hepatitis B. Hepatology 1993; 18:258–263.PubMedCrossRefGoogle Scholar
  116. 116.
    Galban-Garcia E., Vega-Sanchez H., Gra-Oramas B., Jorge-Riano J.L., Soneiras-Perez M., Haedo-Castro D., Rolo-Gomez F., Lorenzo-Morejon I., Ramos-Sanchez V. Efficacy of ribavirin in patients with chronic hepatitis B. J Gastroenterol 2000; 35:347–352.PubMedCrossRefGoogle Scholar
  117. 117.
    Cotonat T., Quiroga J.A., Lopez-Alcorocho J.M., Clouet R., Pardo M., Manzarbeitia F., Carreno V. Pilot study of combination therapy with ribavirin and interferon alfa for the retreatment of chronic hepatitis B e antibody-positive patients. Hepatology 2000;31:502–506.PubMedCrossRefGoogle Scholar
  118. 118.
    Tarn R.C., Ramasamy K., Bard J., Pai B., Lim C, Averett D.R. The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral effects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels. Antimicrob Agents Chemother 2000; 44:1276–1283.PubMedCrossRefGoogle Scholar
  119. 119.
    Houghton M. “Hepatitis C viruses.” In Fields Virology, Fields B.N., Knipe D.M., Howley P.M., eds., New York: Raven Press, 1996; pp 1035–1058.Google Scholar
  120. 120.
    Rice C.M. “Flaviviridae: the viruses and their replication.” In Fields Virology, Fields B.N., Knipe D.M., Howley P.M., eds. New York: Raven Press, 1996; pp 931–960.Google Scholar
  121. 121.
    Seeff L.B. Natural history of hepatitis C. Am J Med 1999; 107:10S–15S.PubMedCrossRefGoogle Scholar
  122. 122.
    Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe T.Y., Koi S., Onji M., Ohta Y., Choo Q.-L., Houghton M., Kuo G. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Sci Acad USA 1990; 87:6547–6549.CrossRefGoogle Scholar
  123. 123.
    World Health Organization. Hepatitis C Seroprevalence of hepatitis C virus (HCV) in a population sample. Wkly Epidemiol Ree 1996; 71:346–349.Google Scholar
  124. 124.
    McHutchison J.G., Gordon S.C., Schiff E.R., Shiftman M.L., Lee W.M., Rustgi V.K., Goodman Z.D., Ling M.H., Cort S., Albrecht J.K. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1485–1492.PubMedCrossRefGoogle Scholar
  125. 125.
    Davis G.L., Esteban-Mur R., Rustgi V., Hoefs J., Gordon S.C., Trepo C., Shiftman M.L., Zeuzem S., Craxi A., Ling M.H., Albrecht J. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339:1493–1499.PubMedCrossRefGoogle Scholar
  126. 126.
    Poynard T., Marcellin P., Lee S.S., Niederau C., Minuk G.S., Ideo G., Bain V., Heathcote J., Zeuzem S., Trepo C., Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352:1426–1432.PubMedCrossRefGoogle Scholar
  127. 127.
    Reichard O., Norkrans G., Fryden A., Braconier J.H., Sonnerborg A., Weiland O., Group T.S.S. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998; 351:83–87.PubMedCrossRefGoogle Scholar
  128. 128.
    Goodbourn S., Didcock L., Randall R.E. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 2000; 81:2341–2364.PubMedGoogle Scholar
  129. 129.
    Davis G.L., Baiart L.A., Schiff E.R., Lindsay K., Bodenheimer H.C.J., Perrillo R.P., Carey W., Jacobson I.M., Payne J., Dienstag J.L.. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med 1989; 321:1501–1506.PubMedCrossRefGoogle Scholar
  130. 130.
    Bartenschlager R. Candidate targets for hepatitis C virus-specific antiviral therapy. Intervirology 1997;40:378–393.PubMedCrossRefGoogle Scholar
  131. 131.
    Davis G.L., Lau J.Y.N. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997; 26:122S–127S.PubMedCrossRefGoogle Scholar
  132. 132.
    Patterson J.L., Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990; 12:1132–1146.Google Scholar
  133. 133.
    Dusheiko G., Main J., Thomas H., Reichard O., Lee C., Dhillon A., Rassam S., Fryden A., Reesink H., Bassendine M., Norkrans G., Cuypers T., Lelie N., Telfer P., Watson J., Weegink C., Sillikens P., Weiland O. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996; 25:591–598.PubMedCrossRefGoogle Scholar
  134. 134.
    Bodenheimer H.C.J., Lindsay K.L., Davis G.L., Lewis J.H., Thung S.N., Seeff L.B. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997; 26:473–477.PubMedCrossRefGoogle Scholar
  135. 135.
    Lee J.H., von Wagner M., Roth W.K., Teuber G., Sarrazin C., Zeuzem S. Effect of ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus. J Hepatol 1998; 29:29–35.PubMedCrossRefGoogle Scholar
  136. 136.
    Ramasamy K.S., Tarn R.C., Bard J., Averett D.R. Monocyclic L-nucleosides with type 1 cytokine-inducing activity. J Med Chem 2000; 43:1019–1028.PubMedCrossRefGoogle Scholar
  137. 137.
    Cramp M.E., Rossol S., Chokshi S., Carucci P., Williams R., Naoumov N.V. Hepatitis C virus-specific T-cell re tctivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology 2000; 118:346–355.PubMedCrossRefGoogle Scholar
  138. 138.
    Lohmann V., Overton H., Bartenschlager R. Selective stimulation of hepatitis C virus and pestivirus NS5B RNA polymerase activity by GTP. J Biol Chem 1999; 274:10807–10815.PubMedCrossRefGoogle Scholar
  139. 139.
    Smith J.P. Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 1997; 42:1681–1687.PubMedCrossRefGoogle Scholar
  140. 140.
    Carlsson T., Lindahl K., Schvarcz R., Wejsta L.R., Uhnoo L., Shev S., Reichard O. HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin. J Virol Hepat 2000; 7:409–413.CrossRefGoogle Scholar
  141. 141.
    Zeuzem S., Teuber G., Naumann U., Berg T., Raedle J., Hartmann S., Hopf U.. Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 2000; 32:835–841.PubMedCrossRefGoogle Scholar
  142. 142.
    Fong T.L., Fried M.W., Clarke-Piatt J. A pilot study of rimantadine for patients with chronic hepatitis C unresponsive to interferon therapy. Am J Gastroenterol 1999; 94:990–993.PubMedCrossRefGoogle Scholar
  143. 143.
    Khalili M., Denham C., Perrillo R. Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C. Am J Gastroenterol 2000;95:1284–1289.PubMedCrossRefGoogle Scholar
  144. 144.
    Jubin R., Murray M.G., Howe A.Y., Butkiewicz N., Hong Z., Lau J.Y. Amantadine and rimantadine have no direct inhibitory effects against hepatitis C viral protease, helicase, ATPase, polymerase, and internal ribosomal entry site-mediated translation. J Infect Dis 2000; 181:331–334.PubMedCrossRefGoogle Scholar
  145. 145.
    O’Brien C.B., Moonka D.K., Henzel B.S. A randomized, double-blind, placebo-controlled study of multiple, ascending doses of recombinant human interleukin-12 (rIL-12) in patients with chronic hepatitis C (HCV) who previously failed therapy with interferon (IFN). Hepatology 1998; 28:574A (Abstract).Google Scholar
  146. 146.
    O’Brien C.B., Henzel B.S., Moonka D.K. Dosing kinetics of single ascending doses of recombinant human interleukin-12 (rIL-12) subcutaneously administered to adults with chronic hepatitis C infection previously treated with interferon-alpha. Hepatology 1998; 28:575A (Abstract).Google Scholar
  147. 147.
    Choo Q.-L., Kuo G., Weiner A.J., Overby L.R., Bradley D.W., Houghton M. Isolation of a cDNA clone derived from a blood-born Non-A, Non-B viral hepatitis genome. Science 1989; 244:359–364.PubMedCrossRefGoogle Scholar
  148. 148.
    Bartenschlager R., Lohmann V. Replication of hepatitis C virus. J Gen Virol 2000; 81:1631–1648.PubMedGoogle Scholar
  149. 149.
    Hong Z., Beaudet-Miller M., Lanford R.E., Guerra B., Wright-Minogue J., Skelton A., Baroudy B.M., Reyes G.R., Lau J.Y.N. Generation of Transmissible Hepatitis C Virions from a Molecular Clone in Chimpanzees. Virolology 1999; 256:36–44.CrossRefGoogle Scholar
  150. 150.
    Kolykhalov A.A., Agapov E.V., Blight K.J., Mihalik K., Feinstone S.M., Rice C.M. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 1997; 277:570–574.PubMedCrossRefGoogle Scholar
  151. 151.
    Yanagi M., Purcell R.H., Emerson S.U., Bukh J. Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee. Proc Natl Acad Sci USA 1997; 94:8738–8743.PubMedCrossRefGoogle Scholar
  152. 152.
    Beard M.R., Abell G., Honda M., Carroll A., Gartland M., Clarke B., Suzuki K., Lanford R., Sangar D.V., Lemon S.M. An infectious molecular clone of a Japanese genotype 1b hepatitis C virus. Hepatology 1999; 30:316–624.PubMedCrossRefGoogle Scholar
  153. 153.
    Yanagi M., Purcell R.H., Emerson S.U., Bukh J. Hepatitis C virus: an infectious molecular clone of a second major genotype (2a) and lack of viability of intertypic la and 2a chimeras. Virology 1999; 262:250–263.PubMedCrossRefGoogle Scholar
  154. 154.
    Lohmann V., Korner F., Koch J.-O., Herian U., Theilmann L., Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999; 285:110–113.PubMedCrossRefGoogle Scholar
  155. 155.
    Pietschmann T., Lohmann V., Rutter G., Kurpanek K., Bartenschlager R. Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 2001;75:1252–1264.PubMedCrossRefGoogle Scholar
  156. 156.
    Blight K.J., Kolykhalov A.A., Rice C.M. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290:1972–1975.PubMedCrossRefGoogle Scholar
  157. 157.
    Lohmann V., Korner F., Dobierzewska A., Bartenschlager R. Mutations in hepatitis C virus RNAs conferring cell culture adaptation. J Virol 2001; 73:1437–1449.CrossRefGoogle Scholar
  158. 158.
    Beames B., Chavez D., Guerra B., Notvall L., Brasky K.M., Lanford R.E. Development of a primary tamarin hepatocyte culture system for GB virus-B: a surrogate model for hepatitis C virus. J. Virol. 2000; 74:11764–11772.PubMedCrossRefGoogle Scholar
  159. 159.
    Muerhoff A.S., Leary T.P., Simons J.N., Pilot-Matias T.J., Dawson G.J., Erker J.C., Chalmers M.L., Schlauder G.G., Desai S.M., Mushahwar I.K. Genomic organization of GB viruses A and B: two new members of the Flaviviridae associated with GB agent hepatitis. J. Virol. 1995; 69:5621–5630.PubMedGoogle Scholar
  160. 160.
    Simons J.N., Pilot-Matias T.J., Leary T.P., Dawson G.J., Desai S.M., Schlauder G.G., Muerhoff A.S., Erker J.C., Buijk S.L., Chalmers M.L., Van Sant C.L., Mushahwar I.K. Identification of two flavivirus-like genomes in the GB hepatitis agent. Proc Natl Acad Sci USA 1995; 92:3401–3405.PubMedCrossRefGoogle Scholar
  161. 161.
    Bukh J., Apgar C.L., Yanagi M. Toward a surrogate model for hepatitis C virus: an infectious molecular clone of the GB virus-B hepatitis agent. Virology 1999; 262:470–478.PubMedCrossRefGoogle Scholar
  162. 162.
    Mendez E., Ruggli N., Collett M.S., Rice C.M. Infectious bovine viral diarrhea virus (strain NADL) RNA from stable cDNA clones: a cellular insert determines NS3 production and viral cytopathogenicity. J Virol 1998; 72:4737–4745.PubMedGoogle Scholar
  163. 163.
    Vassilev V.B., Collett M.S., Donis R.O. Authentic and chimeric full-length genomic cDNA clones of bovine viral diarrhea virus that yield infectious transcripts. J Virol 1997;71:471–478.PubMedGoogle Scholar
  164. 164.
    Collett M.S., Larson R., Gold C., Strick D., Anderson D.K., Purchio A.F. Molecular cloning and nucleotide sequence of the pestivirus bovine viral diarrhea virus. Virology 1988; 165:191–199.CrossRefGoogle Scholar
  165. 165.
    Failla C., Tomei L., De Francesco R. Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol 1994; 68:3753–3760.PubMedGoogle Scholar
  166. 166.
    Kim J.L., Morgenstern K.A., Lin C., Fox T., Dwyer M.D., Landro J.A., Chambers S.P., Markland W., Lepre C.A., O’Malley E.T., Harbeson S.L., Rice C.M., Murcko M.A., Caron P.R., Thomson J.A. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996; 87:343–355.PubMedCrossRefGoogle Scholar
  167. 167.
    Lin C., Thomson J.A., Rice C.M. A central region in the hepatitis C virus NS4A protein allows formation of an active NS3-NS4A serine proteinase complex in vivo and in vitro. J Virol 1995; 69:4373–4380.PubMedGoogle Scholar
  168. 168.
    Bartenschlager R., Ahlborn-Laake L., Mous J., Jacobsen H. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. J Virol 1993; 67:3835–3844.PubMedGoogle Scholar
  169. 169.
    Grakoui A., McCourt D.W., Wychowski C., Feinstone S.M., Rice C.M. Characterization of the hepatitis C virus-encoded serine proteinase: determination of the proteinase-dependent polyprotein cleavage sites. J Virol 1993; 67:2832–2843.PubMedGoogle Scholar
  170. 170.
    Hijikata M., Mizushima H., Akagi T., Mori S., Kakiuchi N., Kato N., Tanaka T., Kimura K., Shimotohno K. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 1993;67:4665–4675.PubMedGoogle Scholar
  171. 171.
    Steinkuhler C., Urbani A., Tomei L., Biasiol G., Sardana M., Bianchi E., Pessi A., De Francesco R. Activity of purified hepatitis C virus protease NS3 on peptide substrates. J Virol 1996; 70:6694–6700.PubMedGoogle Scholar
  172. 172.
    Kolykhalov A.A., Mihalik K., Feinstone S.M., Rice C.M. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J Virol 2000; 74:2046–2051.PubMedCrossRefGoogle Scholar
  173. 173.
    Love R.A., Parge H.E., Wickersham J.A., Hostomsky Z., Habuka N., Moomaw E.W., Adachi T., Hostomska Z. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 1996; 87:331–342.PubMedCrossRefGoogle Scholar
  174. 174.
    Yan Y., Li Y., Munshi S., Sardana V., Cole J.L., Sardana M., Steinkuehler C., Tomei L., De Francesco R., Kuo L.C., Chen Z. Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 A resolution structure in a hexagonal crystal form. Protein Sci 1998; 7:837–847.PubMedCrossRefGoogle Scholar
  175. 175.
    Yao N., Reichert P., Taremi S., Prosise W. W., Weber P.C. Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease-helicase. Structure 1999; 7:1353–1363.PubMedCrossRefGoogle Scholar
  176. 176.
    De Francesco R., Urbani A., Nardi M.C., Tomei L., Steinkuhler C., Tramontano A. A zinc binding site in viral serine proteinases. Biochem 1996; 35:13282–13287.CrossRefGoogle Scholar
  177. 177.
    Sali D.L., Ingram R., Wendel M., Gupta D., McNemar C., Tsarbopoulos A., Chen J.W., Hong Z., Chase R., Risano C., Zhang R., Yao N., Kwong A.D., Ramanathan L., Le H. V., Weber P.C. Serine protease of hepatitis C virus expressed in insect cells as the NS3/4A complex. Biochem 1998; 37:3392–3401.CrossRefGoogle Scholar
  178. 178.
    Narjes F., Brunetti M., Colarusso S., Gerlach B., Koch U., Biasiol G., Fattori D., De Francesco R., Matassa V.G., Steinkuhler C. Alpha-ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease. Biochemistry 2000; 39:1849–1861.PubMedCrossRefGoogle Scholar
  179. 179.
    Ingallinella P., Altamura S., Bianchi E., Taliani M., Ingenito R., Cortese R., De Francesco R., Steinkuhler C., Pessi A. Potent peptide inhibitors of human hepatitis C virus NS3 protease are obtained by optimizing the cleavage products. Biochem 1998; 37:8906–8914.CrossRefGoogle Scholar
  180. 180.
    Steinkuhler C., Biasiol G., Brunetti M., Urbani A., Koch U., Cortese R., Pessi A., De Francesco R. Product inhibition of the hepatitis C virus NS3 protease. Biochem 1998; 37:8899–8905.CrossRefGoogle Scholar
  181. 181.
    Bianchi E., Orru S., Dal Piaz F., Ingenito R., Casbarra A., Biasiol G., Koch U., Pucci P., Pessi A. Conformational changes in human hepatitis C virus NS3 protease upon binding of product-based inhibitors. Biochemistry 1999; 38:13844–13852.PubMedCrossRefGoogle Scholar
  182. 182.
    Sudo K., Matsumoto Y., Matsushima M., Konno K., Shimotohno K., Shigeta S., Yotoka T. Novel HCV protease inhibitors: 2,4,6-trihydroxy-3-nitro-benzamide derivatives. Antiviral Chemistry and Chemotherapy 1997; 8:541–544.Google Scholar
  183. 183.
    Sudo K., Matsumoto Y., Matsushima M., Fujiwara M., Konno K., Shimotohno K., Shigeta S., Yokota T. Novel hepatitis C virus protease inhibitors: thiazolidine derivatives. Biochem Biophys Res Commun 1997; 238:643–647.PubMedCrossRefGoogle Scholar
  184. 184.
    Kakiuchi N., Komoda Y., Komoda K., Takeshita N., Okada S., Tani T., Shimotohno K. Non-peptide inhibitors of HCV serine proteinase. FEBS Letters 1998; 421:217–220.PubMedCrossRefGoogle Scholar
  185. 185.
    Takeshita N., Kakiuchi N., Kanazawa T., Komoda Y., Nishizawa M., Tani T., Shimotohno K. An enzyme-linked immunosorbent assay for detecting proteolytic activity of hepatitis C virus proteinase. Anal Biochem 1997; 247:242–246.PubMedCrossRefGoogle Scholar
  186. 186.
    Chu M., Mierzwa R., He L., King A., Patel M., Pichardo J., Hart A., Butkiewicz N., Puar M.S. Isolation and structure of Sch 351633: a novel (HCV) NS3 serine protease inhibitor from the fungus Penicillium griseofulvum. Bioorganic and Medicinal Chemistry Letters 1999; 9:1949–1952.PubMedCrossRefGoogle Scholar
  187. 187.
    Chu M., Mierzwa R., Truumees I., King A., Patel M., Berne R., Hart A., Butkiewicz N., Dasmahapatra B., Chan T., Puar M.S. Structure of Sch 68631: a new HCV proteinase inhibitor from Streptomyces sp. Tetrahedron Letters 1996; 37:7229–7232.CrossRefGoogle Scholar
  188. 188.
    Kim D.W., Gwack Y., Han J.H., Choe J. C-terminal domain of the hepatitis C virus NS3 protein contains an RNA helicase activity. Biochem Biophys Res Commun 1995; 215:160–166.PubMedCrossRefGoogle Scholar
  189. 189.
    Kim D.W., Kim J., Gwack Y., Han J.H., Choe J. Mutational analysis of the hepatitis C virus RNA helicase. J Virol 1997; 71:9400–9409.PubMedGoogle Scholar
  190. 190.
    Kim D.W., Gwack Y., Han J.H, Choe J. Towards defining a minimal functional domain for NTPase and RNA helicase activities of the hepatitis C virus NS3 protein. Virus Res 1997; 49:17–25.PubMedCrossRefGoogle Scholar
  191. 191.
    Suzich J.A., Tamura J.K., Palmer-Hill F., Warrener P., Grakoui A., Rice C.M., Feinstone S.M., Collett M.S. Hepatitis C virus NS3 protein polynucleotide-stimulated nucleoside triphosphatase and comparison with the related pestivirus and flavivirus enzymes. J Virol 1993; 67:6152–6158.PubMedGoogle Scholar
  192. 192.
    Tai C.L., Chi W.K., Chen D.S., Hwang L.H. The helicase activity associated with hepatitis C virus nonstructural protein 3. J Virol 1996; 70:8477–8484.PubMedGoogle Scholar
  193. 193.
    Gwack Y., Kim D.W., Han J.H., Choe J. Characterization of RNA binding activity and RNA helicase activity of the hepatitis C virus NS3 protein. Biochem Biophys Res Commun 1996; 225:654–659.PubMedCrossRefGoogle Scholar
  194. 194.
    Hong Z., Ferrari E., Wright-Minogue J., Chase R., Risano C., Seelig G., Lee C-G., Kwong A.D. Enzymatic characterization of hepatitis C virus NS3/4A complexes expressed in mammalian cells using the herpes simplex virus amplicon system. J Virol 1996; 70:4261–4268.PubMedGoogle Scholar
  195. 195.
    Gu B., Liu C., Lin-Goerke J., Maley D.R., Gutshall L.L., Feltenberger C.A., Del Vecchio A.M. The RNA helicase and nucleotide triphosphatase activities of the bovine viral diarrhea virus NS3 protein are essential for viral replication. J Virol 2000; 74:1794–1800.PubMedCrossRefGoogle Scholar
  196. 196.
    Grassmann C.W., Isken O., Behrens S.-E. Assignment of the multifunctional NS3 protein of bovine viral diarrhea virus during RNA replication: an in vitro and in vivo study. J Virol 1999; 73:9196–9205.PubMedGoogle Scholar
  197. 197.
    Kim J.L., Morgenstern K.A., Griffith J.P., Dwyer M.D., Thomson J.A., Murcko M.A., Lin C., Caron P.R. Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure 1998; 6:89–100.PubMedCrossRefGoogle Scholar
  198. 198.
    Yao N., Hesson T., Cable M., Hong Z., Kwong A.D., Le H.V., Weber P.C. Structure of the hepatitis C virus RNA helicase domain. Nature Struct Biol 1997; 4:463–467.PubMedCrossRefGoogle Scholar
  199. 199.
    Diana G.D., Bailey T.R., Nitz T.J. 1997; W097/36554.Google Scholar
  200. 200.
    Diana G.D., Bailey T.R. 1997; US Patent 5, 633, 388.Google Scholar
  201. 201.
    Lesburg C.A., Cable M.B., Ferrari E., Hong Z., Mannarino A.F., Weber P.C. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nature Struct Biol 1999; 6:937–943.PubMedCrossRefGoogle Scholar
  202. 202.
    Bressanelli S., Tomei L., Roussel A., Incitti L., Vitale R.L., Mathieu M., De Francesco R., Rey F. A. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc Natl Acad Sci USA 1999; 96:13034–13039.PubMedCrossRefGoogle Scholar
  203. 203.
    Ago H., Adachi T., Yoshida A., Yamamoto M., Habuka N., Yatsunami K., Miyano M. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure Fold Des 1999; 7:1417–26.PubMedCrossRefGoogle Scholar
  204. 204.
    Ferrari E., Wright-Minogue J., Fang J.W.S., Baroudy B.M., Lau J.Y.N., Hong Z. Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expressed in Escherichia coli. J Virol 1999; 73:1649–1654.PubMedGoogle Scholar
  205. 205.
    Behrens S.-E., Tomei L., De Francesco R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J 1996; 15:12–22.PubMedGoogle Scholar
  206. 206.
    Ishii K., Tanaka Y., Yap C.C., Aizaki H., Matsuura Y., Miyamura T. Expression of hepatitis C virus NS5B protein: characterization of its RNA polymerase activity and RNA binding. Hepatology 1999; 29:1227–35.PubMedCrossRefGoogle Scholar
  207. 207.
    Lohmann V., Korner F., Herian U., Bartenschlager R. Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J Virol 1997; 71:8416–8428.PubMedGoogle Scholar
  208. 208.
    Lohmann V., Roos A., Korner F., Koch J.O., Bartenschlager R. Biochemical and kinetic analyses of NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Virology 1998; 249:108–118.PubMedCrossRefGoogle Scholar
  209. 209.
    Oh J.W., Ito T., Lai M.M. A recombinant hepatitis C virus RNA-dependent RNA polymerase capable of copying the full-length viral RNA. J Virol 1999; 73:7694–702.PubMedGoogle Scholar
  210. 210.
    Zhong W., Uss A.S., Ferrari E., Lau J.Y., Hong Z. De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. J Virol 2000; 74:2017–22.PubMedCrossRefGoogle Scholar
  211. 211.
    Zhong W., Ingravallo P., Wright-Minogue J., Uss A.S., Skelton A., Ferrari E., Lau J.Y., Hong Z. Template/primer requirements and single nucleotide incorporation by hepatitis C virus nonstructural protein 5B polymerase. J Virol 2000; 74:9134–9143.PubMedCrossRefGoogle Scholar
  212. 212.
    Hong Z., Cameron CE., Lau J.Y.N., Zhong W. Hepatitis C virus NS5B polymerase employs a novel mechanism to ensure terminal initiation during replication. 2001; Submitted.Google Scholar
  213. 213.
    Hijikata M., Mizushima H., Tanji Y., Komoda Y., Hirowatari Y., Akagi T., Kato N., Kimura K., Shimotohno K. Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus. Proc Natl Acad Sci USA 1993; 90:10773–10777.PubMedCrossRefGoogle Scholar
  214. 214.
    Pieroni L., Santolini E., Fipaldini C., Pacini L., Migliaccio G., La Monica N. In vitro study of the NS2-3 protease of hepatitis C virus. J Virol 1997; 71:6373–6380.PubMedGoogle Scholar
  215. 215.
    Wu Z., Yao N., Le H., Weber P.C. Mechanism of autoproteolysis at the NS2-NS3 junction of the hepatitis C virus polyprotein. TIBS 1998; 23:92–94.PubMedGoogle Scholar
  216. 216.
    Agnello V., Abel G., Elfahal M., Knight G.B., Zhang Q.-X. Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 1999; 96:12766–12771.PubMedCrossRefGoogle Scholar
  217. 217.
    Pileri P., Uematsu Y., Campagnoli S., Galli G., Falugi F., Petracca R., Weiner A.J., Houghton M., Rosa D., Grandi G., Abrignani S. Binding of Hepatitis C Virus to CD81. Science 1998; 282:938–941.PubMedCrossRefGoogle Scholar
  218. 218.
    Tsukiyama-Kohara K., Iizuka N., Kohara M., Nomoto A. Internal ribosome entry site within hepatitis C virus RNA. J Virol 1992; 66:1476–1483.PubMedGoogle Scholar
  219. 219.
    Roberts E.C., Malmstrom T.A., Pavco P.A. Synthesis and testing of nuclease resistant hammerhead ribozymes directed against hepatitis C virus RNA. Hepatology 1998; 28.398A.Google Scholar
  220. 220.
    Macejak D.G., Jensen K.L., Bellon L., Pavco P.A., Blatt L.M. Inhibition of viral replication by nuclease resistant hammerhead ribozymes directed against hepatitis C virus RNA. Hepatology 1999; 30:abstract 995.Google Scholar
  221. 221.
    Macejak D.G., Jensen KL, F. J. S., Domenico K., Roberts E.C., Chaudhary N., von Carlowitz I., Bellon L., Tong M.J., Conrad A., Pavco P.A., Blatt L.M. Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes. Hepatology 2000; 31:769–776.PubMedCrossRefGoogle Scholar
  222. 222.
    Lee P.A., Blatt L.M., Blanchard K.S., Bouhana K.S., Pavco P.A., Bellon L., Sandberg J.A. Pharmacokinetics and tissue distribution of a ribozyme directed against hepatitis C virus RNA following subcutaneous or intravenous administration in mice. Hepatology 2000; 32:640–646.PubMedCrossRefGoogle Scholar
  223. 223.
    Ikeda M., Sakai T., Tsuai S., Zuao I., Ryan H., Iyan S., Kai Y., Kako Y., Tsukada I., YanagisawaM. 1996; JP-08268890.Google Scholar
  224. 224.
    Kai Y., Sasho M., Kaku Y., Tsukada I., Yanagisawa M. 1996; JP-1010591.Google Scholar
  225. 225.
    Crotty S., Maag D., Arnold J.J., Zhong W., Lau J. Y., Hong Z., Andino R., Cameron C.E. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nature Medicine 2000; 6:1375–1379.PubMedCrossRefGoogle Scholar
  226. 226.
    Lau J.Y., King R., Tibbs C.J., Catterall A.P., Smith H.M., Portmann B.C., Alexander G.J., Williams R. Loss of HBsAg with interferon-alpha therapy in chronic hepatitis D virus infection. J Med Virol 1993; 39:292–296.PubMedCrossRefGoogle Scholar
  227. 227.
    Hoofhagle J.H. Therapy of acute and chronic viral hepatitis. Adv Intern Med 1994; 39:241–275.Google Scholar
  228. 228.
    Saracco G., Rizzetto M. A practical guide to the use of interferons in the management of hepatitis virus infections. Drugs 1997; 53:74–85.PubMedCrossRefGoogle Scholar
  229. 229.
    Battegay M., Simpson L.H., Hoofhagle J.H., Sallie R., Di Bisceglie A.M. Elimination of hepatitis delta virus infection after loss of hepatitis B surface antigen in patients with chronic delta hepatitis. J Med Virol 1994; 44:389–92.PubMedCrossRefGoogle Scholar
  230. 230.
    Lau D.T., Doo E., Park Y., Kleiner D.E., Schmid P., Kuhns M.C., Hoofhagle J.H. Lamivudine for chronic delta hepatitis. Hepatology 1999; 30:546–9.PubMedCrossRefGoogle Scholar
  231. 231.
    Wolters L.M., van Nunen A.B., Honkoop P., Vossen A.C., Niesters H.G., Zondervan P.E., de Man R.A. Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus. J Viral Hepat 2000; 7:428–34.PubMedCrossRefGoogle Scholar
  232. 232.
    Glenn J.S., Watson J.A., Havel C.M., White J.M. Identification of a prenylation site in delta virus large antigen. Science 1992; 256:1331–1333.PubMedCrossRefGoogle Scholar
  233. 233.
    Marsters J.C., Jr., McDowell R.S., Reynolds M.E., Oare D.A., Somers T.C., Stanley M.S., Rawson T.E., Struble M.E., Burdick D.J., Chan K.S., et al. 1994; Benzodiazepine peptidomimetic inhibitors of farnesyl-transferase. Bioorg Med Chem 2:949–957.PubMedCrossRefGoogle Scholar
  234. 234.
    Glenn J.S., Marsters J.C., Jr., Greenberg H.B. Use of a prenylation inhibitor as a novel antiviral agent. J Virol 1998; 72:9303–9306.PubMedGoogle Scholar
  235. 235.
    Fattovich G., Boscaro S., Noventa F., Pomaro E., Stenico D., Alberti A., Ruol A., Realdi G. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis 1997; 155:931–935.CrossRefGoogle Scholar
  236. 236.
    Samuel D., Zignego A.L., Reynes M., Feray C., Arulnaden J.L., David M.F., Gigou M., Bismuth A., Mathieu D., Gentilini P., Benhamou J., Brechot C., Bismuth H. Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis. Hepatology 1995; 21:333–9.PubMedCrossRefGoogle Scholar
  237. 237.
    Marzano A., Salizzoni M., Rizzetto M. Liver transplantation in viral hepatitis. New insights. Acta Gastroenterol Belg 1999; 62:342–347.PubMedGoogle Scholar
  238. 238.
    Bradley D.W. Hepatitis E: Epidemiology, aetiology and molecular biology. Med Virol 1992; 2:19–28.CrossRefGoogle Scholar
  239. 239.
    Hyams K.C, Yarbough P.O., Gray S., Callahan J., Gotuzzo E., Gutierrez J., Vasquez P.B., Hayes C.G., Watts D.M. Hepatitis E virus infection in Peru. Clin Infect Dis 1996; 22. 240CrossRefGoogle Scholar
  240. 240.
    Pujol F.H., Favarov M.O., Marcaano T., Este J.A., Magris M., Liprandi F., Khudyakov Y.E., Khydyakova N.S., Fields H.A. Prevalence of antibodies against Hepatitis E virus among urban and rural populations in Venezuela. J Med Virol 1994; 42.Google Scholar
  241. 241.
    Quiroga J.A., Cotonat T., Castillo I., Carreno V. Hepatitis E virus seroprevalence in acute viral hepatitis in a developed country confirmed by a supplemental assay. J Med Virol 1996; 50:16–19.PubMedCrossRefGoogle Scholar
  242. 242.
    Zaaijer J.L., Kok M., Lehe P.N., Timmerman R.J., Chau K., van der Pal H.J.H. Hepatitis E in the Netherlands: Imported and endemic. Lancet 1993; 341:826.PubMedCrossRefGoogle Scholar
  243. 243.
    Purcell R.H., Ticehurst J.R. “Enterically transmitted non-A, non-B hepatitis: epidemiology and clinical characteristics.”. In Viral Hepatitis and Liver Disease, Zuckerman A., ed., New York: Alan R. Liss, 1988; pp 131–137.Google Scholar
  244. 244.
    Joshi Y.K., Babu S., Sarin S., Tandon B.N., Gandhi B.M., Chaturvedi V.C Immunoprophylaxis of epidemic non-A non-B hepatitis. Indian J Med Res 1985; 81:18–19.PubMedGoogle Scholar
  245. 245.
    Khuroo M.S., Dar M.Y. Hepatitis E: evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 1992; 11:113–116.PubMedGoogle Scholar
  246. 246.
    Reyes G.R., Purdy M.A., Kim J., Luk K.C., Young L.M., Fry K.M., Bradley D.W. Isolation of cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. Science 1990; 247:1335–1339.PubMedCrossRefGoogle Scholar
  247. 247.
    Tarn A.W., Smith M.M., Guerra M.E., Huang C.C., Bradley D.W., Fry K.E., Reyes G.R. Hepatitis E Virus (HEV): Molecular cloning and sequencing of the full-length viral genome. Virology 1991; 185:120–131.CrossRefGoogle Scholar
  248. 248.
    Purdy M.A., McCaustland K.A., Krawezynski K., Spelbring J., Reyes G.R., Bradley D.W. Preliminary evidence that a trpE-HEV fusion protein protects cynomolgus macaques against challenge with wild-type hepatitis E virus (HEV). J Med Virol 1993;41:90–94.PubMedCrossRefGoogle Scholar
  249. 249.
    Yarbough P.O., Krawezynski K., Tarn A.W., McAtee C.P., McCaustland K.A., Zhang Y., Garçon N., Spellbring J., Carson D., Myriam F., Lifson J.D., Slaoui M., Prieels J.P., Margolis H., Fuerst T.R. “Prevention of hepatitis E using r62K subunit vaccine: Full protection against heterologous HEV challenge in cynomolgus macaques.” In Viral Hepatitis and Liver Disease, Rizzetto M., Purcell R.H., Gerin J.L., Verme G., eds., Turin: Turin Edizioni Minerva Medica, 1997; pp 650–655.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Robert K. Hamatake
    • 1
  • Zhi Hong
    • 1
  • Johnson Y. N. Lau
    • 1
  • Weidong Zhong
    • 1
  1. 1.ICN PharmaceuticalsCosta MesaUSA

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