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J Gen Virol 74 (1993), 2391-2399; DOI 10.1099/0022-1317-74-11-2391
© 1993 Society for General Microbiology

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Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region

P. Simmonds1, E. C. Holmes2,{dagger}, T.-A. Cha3,{ddagger}, S.-W. Chan1, F. McOmish4, B. Irvine3, E. Beall3,||, P. L. Yap4, J. Kolberg3 and M. S. Urdea3

1 Department of Medical Microbiology, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, U.K.
2 Division of Biology, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JN, U.K.
3 Chiron Corporation, 4560 Horton Street, Emeryville, California 94608, U.S.A.
and4 Edinburgh and South East Scotland Blood Transfusion Service, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh EH3 9HB, U.K.

Hepatitis C virus (HCV) shows substantial nucleotide sequence diversity distributed throughout the viral genome, with many variants showing only 68 to 79% overall sequence similarity to one another. Phylogenetic analysis of nucleotide sequences derived from part of the gene encoding a non-structural protein (NS-5) has provided evidence for six major genotypes of HCV amongst a worldwide collection of 76 samples from HCV-infected blood donors and patients with chronic hepatitis. Many of these HCV types comprised a number of more closely related subtypes, leading to a current total of 11 genetically distinct viral populations. Phylogenetic analysis of other regions of the viral genome produced relationships between published sequences equivalent to those found in NS-5, apart from the more highly conserved 5' non-coding region in which only the six major HCV types, but not subtypes, could be differentiated. A new nomenclature for HCV variants is proposed in this communication that reflects the two-tiered nature of sequence differences between different viral isolates. The scheme classifies all known HCV variants to date, and describes criteria that would enable new variants to be assigned within the classification as they are discovered.

{dagger} Present address: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K.

{ddagger} Present address: Aviron, Belmont, California, U.S.A.

|| Present address: Department of Biochemistry, University of California, Berkeley, California 94720, U.S.A.

Received 17 August 1993; accepted 19 August 1993.


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R. Jubin, N. E. Vantuno, J. S. Kieft, M. G. Murray, J. A. Doudna, J. Y. N. Lau, and B. M. Baroudy
Hepatitis C Virus Internal Ribosome Entry Site (IRES) Stem Loop IIId Contains a Phylogenetically Conserved GGG Triplet Essential for Translation and IRES Folding
J. Virol., November 15, 2000; 74(22): 10430 - 10437.
[Abstract] [Full Text]


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J. Gen. Virol.Home page
R. Bartenschlager and V. Lohmann
Replication of hepatitis C virus
J. Gen. Virol., July 1, 2000; 81(7): 1631 - 1648.
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J. Gen. Virol.Home page
K. Abid, R. Quadri, A.-L. Veuthey, A. Hadengue, and F. Negro
A novel hepatitis C virus (HCV) subtype from Somalia and its classification into HCV clade 3
J. Gen. Virol., June 1, 2000; 81(6): 1485 - 1493.
[Abstract] [Full Text]


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ANN INTERN MEDHome page
H. Zylberberg, M. L. Chaix, and C. Brechot
Infection with Hepatitis C Virus Genotype 4 Is Associated with a Poor Response to Interferon-{alpha}
Ann Intern Med, May 16, 2000; 132(10): 845 - 846.
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Clin. Microbiol. Rev.Home page
N. N. Zein
Clinical Significance of Hepatitis C Virus Genotypes
Clin. Microbiol. Rev., April 1, 2000; 13(2): 223 - 235.
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J. Clin. Microbiol.Home page
P. A. White, X. Zhai, I. Carter, Y. Zhao, and W. D. Rawlinson
Simplified Hepatitis C Virus Genotyping by Heteroduplex Mobility Analysis
J. Clin. Microbiol., February 1, 2000; 38(2): 477 - 482.
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J. Gen. Virol.Home page
V. Barban, S. Fraysse-Corgier, G. Paranhos-Baccala, M. Petit, C. Manin, Y. Berard, A. M. Prince, B. Mandrand, and P. Meulien
Identification of a human epitope in hepatitis C virus (HCV) core protein using a molecularly cloned antibody repertoire from a non-symptomatic, anti-HCV-positive patient
J. Gen. Virol., February 1, 2000; 81(2): 461 - 469.
[Abstract] [Full Text]


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GutHome page
P H McGuinness, D Painter, S Davies, and G W McCaughan
Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection
Gut, February 1, 2000; 46(2): 260 - 269.
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J. Virol.Home page
G. Luo, R. K. Hamatake, D. M. Mathis, J. Racela, K. L. Rigat, J. Lemm, and R. J. Colonno
De Novo Initiation of RNA Synthesis by the RNA-Dependent RNA Polymerase (NS5B) of Hepatitis C Virus
J. Virol., January 1, 2000; 74(2): 851 - 863.
[Abstract] [Full Text]


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Nephrol Dial TransplantHome page
D. Marchesi, E. Minola, and O. Vicari
Apparent epidemic of HCV infection in a haemodialysis unit
Nephrol. Dial. Transplant., January 1, 2000; 15(1): 133 - 134.
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J. Mol. Diagn.Home page
S. D. Finkelstein, R. Dhir, M. Rabinovitz, M. Bischeglia, P. A. Swalsky, P. DeFlavia, J. Woods, A. Bakker, and M. Becich
Cold-Temperature Plastic Resin Embedding of Liver for DNA- and RNA-Based Genotyping
J. Mol. Diagn., November 1, 1999; 1(1): 17 - 22.
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J. Gen. Virol.Home page
R. N. Charrel, P. De Micco, and X. de Lamballerie
Phylogenetic analysis of GB viruses A and C: evidence for cospeciation between virus isolates and their primate hosts
J. Gen. Virol., September 1, 1999; 80(9): 2329 - 2335.
[Abstract] [Full Text]


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NEJMHome page
M. J. Alter, D. Kruszon-Moran, O. V. Nainan, G. M. McQuillan, F. Gao, L. A. Moyer, R. A. Kaslow, and H. S. Margolis
The Prevalence of Hepatitis C Virus Infection in the United States, 1988 through 1994
N. Engl. J. Med., August 19, 1999; 341(8): 556 - 562.
[Abstract] [Full Text] [PDF]


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J. Clin. Microbiol.Home page
M. Schröter, H.-H. Feucht, P. Schäfer, B. Zöllner, and R. Laufs
Serological Determination of Hepatitis C Virus Subtypes 1a, 1b, 2a, 2b, 3a, and 4a by a Recombinant Immunoblot Assay
J. Clin. Microbiol., August 1, 1999; 37(8): 2576 - 2580.
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J. Clin. Microbiol.Home page
J. J. Germer, P. N. Rys, J. N. Thorvilson, and D. H. Persing
Determination of Hepatitis C Virus Genotype by Direct Sequence Analysis of Products Generated with the Amplicor HCV Test
J. Clin. Microbiol., August 1, 1999; 37(8): 2625 - 2630.
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J. Clin. Microbiol.Home page
K. Aoyagi, C. Ohue, K. Iida, T. Kimura, E. Tanaka, K. Kiyosawa, and S. Yagi
Development of a Simple and Highly Sensitive Enzyme Immunoassay for Hepatitis C Virus Core Antigen
J. Clin. Microbiol., June 1, 1999; 37(6): 1802 - 1808.
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J. Virol.Home page
M. Honda, R. Rijnbrand, G. Abell, D. Kim, and S. M. Lemon
Natural Variation in Translational Activities of the 5' Nontranslated RNAs of Hepatitis C Virus Genotypes 1a and 1b: Evidence for a Long-Range RNA-RNA Interaction outside of the Internal Ribosomal Entry Site
J. Virol., June 1, 1999; 73(6): 4941 - 4951.
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J. Virol.Home page
S. Tang, A. J. Collier, and R. M. Elliott
Alterations to both the Primary and Predicted Secondary Structure of Stem-Loop IIIc of the Hepatitis C Virus 1b 5' Untranslated Region (5'UTR) Lead to Mutants Severely Defective in Translation Which Cannot Be Complemented in trans by the Wild-Type 5'UTR Sequence
J. Virol., March 1, 1999; 73(3): 2359 - 2364.
[Abstract] [Full Text]


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J. Virol.Home page
M. Honda, M. R. Beard, L.-H. Ping, and S. M. Lemon
A Phylogenetically Conserved Stem-Loop Structure at the 5' Border of the Internal Ribosome Entry Site of Hepatitis C Virus Is Required for Cap-Independent Viral Translation
J. Virol., February 1, 1999; 73(2): 1165 - 1174.
[Abstract] [Full Text]


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J. Immunol.Home page
M. Shirai, T. Arichi, M. Chen, M. Nishioka, K. Ikeda, H. Takahashi, N. Enomoto, T. Saito, M. E. Major, T. Nakazawa, et al.
T Cell Recognition of Hypervariable Region-1 from Hepatitis C Virus Envelope Protein with Multiple Class II MHC Molecules in Mice and Humans: Preferential Help for Induction of Antibodies to the Hypervariable Region
J. Immunol., January 1, 1999; 162(1): 568 - 576.
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J. Virol.Home page
D. G. Sullivan, J. J. Wilson, R. L. Carithers Jr., J. D. Perkins, and D. R. Gretch
Multigene Tracking of Hepatitis C Virus Quasispecies after Liver Transplantation: Correlation of Genetic Diversification in the Envelope Region with Asymptomatic or Mild Disease Patterns
J. Virol., December 1, 1998; 72(12): 10036 - 10043.
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J. Clin. Microbiol.Home page
Y.-M. Wang, S. C. Ray, O. Laeyendecker, J. R. Ticehurst, and D. L. Thomas
Assessment of Hepatitis C Virus Sequence Complexity by Electrophoretic Mobilities of Both Single-and Double-Stranded DNAs
J. Clin. Microbiol., October 1, 1998; 36(10): 2982 - 2989.
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J. Clin. Microbiol.Home page
M. Beld, M. Penning, M. van Putten, A. van den Hoek, V. Lukashov, M. McMorrow, and J. Goudsmit
Hepatitis C Virus Serotype-Specific Core and NS4 Antibodies in Injecting Drug Users Participating in the Amsterdam Cohort Studies
J. Clin. Microbiol., October 1, 1998; 36(10): 3002 - 3006.
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J. Clin. Microbiol.Home page
S. Le Pogam, D. Le Chapois, R. Christen, F. Dubois, F. Barin, and A. Goudeau
Hepatitis C in a Hemodialysis Unit: Molecular Evidence for Nosocomial Transmission
J. Clin. Microbiol., October 1, 1998; 36(10): 3040 - 3043.
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CVIHome page
S. Songsivilai, D. Kanistanon, and T. Dharakul
A Serotyping Assay for Hepatitis C Virus in Southeast Asia
Clin. Vaccine Immunol., September 1, 1998; 5(5): 737 - 739.
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J. Clin. Microbiol.Home page
L.-J. van Doorn, C. Figueiredo, R. Sanna, S. Pena, P. Midolo, E. K. W. Ng, J. C. Atherton, M. J. Blaser, and W. G. V. Quint
Expanding Allelic Diversity of Helicobacter pylori vacA
J. Clin. Microbiol., September 1, 1998; 36(9): 2597 - 2603.
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J. Clin. Microbiol.Home page
S. Le Pogam, F. Dubois, R. Christen, C. Raby, A. Cavicchini, and A. Goudeau
Comparison of DNA Enzyme Immunoassay and Line Probe Assays (Inno-LiPA HCV I and II) for Hepatitis C Virus Genotyping
J. Clin. Microbiol., May 1, 1998; 36(5): 1461 - 1463.
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Clin. Microbiol. Rev.Home page
P. Muir, U. Kammerer, K. Korn, M. N. Mulders, T. Poyry, B. Weissbrich, R. Kandolf, G. M. Cleator, and A. M. van Loon
Molecular Typing of Enteroviruses: Current Status and Future Requirements
Clin. Microbiol. Rev., January 1, 1998; 11(1): 202 - 227.
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J. Clin. Microbiol.Home page
P. Calvo, J Kansopon, K Sra, S Quan, R DiNello, R Guaschino, G Calabrese, F Danielle, M. Brunetto, F Bonino, et al.
Hepatitis C virus heteroduplex tracking assay for genotype determination reveals diverging genotype 2 isolates in Italian hemodialysis patients [In Process Citation]
J. Clin. Microbiol., January 1, 1998; 36(1): 227 - 233.
[Abstract] [Full Text]


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BloodHome page
V. Di Marco, O. L. Iacono, P. Almasio, C. Ciaccio, M. Capra, M. Rizzo, R. Malizia, A. Maggio, C. Fabiano, F. Barbaria, et al.
Long-Term Efficacy of alpha -Interferon in beta -Thalassemics With Chronic Hepatitis C
Blood, September 15, 1997; 90(6): 2207 - 2212.
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BloodHome page
S. Cesaro, M. G. Petris, F. Rossetti, R. Cusinato, C. Pipan, M. Guido, L. Masiero, G. A. Botta, G. A. Meloni, and L. Zanesco
Chronic Hepatitis C Virus Infection After Treatment for Pediatric Malignancy
Blood, August 1, 1997; 90(3): 1315 - 1320.
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BloodHome page
S. De Vita, C. Sacco, D. Sansonno, A. Gloghini, F. Dammacco, M. Crovatto, G. Santini, R. Dolcetti, M. Boiocchi, A. Carbone, et al.
Characterization of Overt B-Cell Lymphomas in Patients With Hepatitis C Virus Infection
Blood, July 15, 1997; 90(2): 776 - 782.
[Abstract] [Full Text] [PDF]


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NEJMHome page
S. Vento, L. Guella, and E. Concia
Discordant Manifestations of Hepatitis C in Monozygotic Twins
N. Engl. J. Med., November 2, 1995; 333(18): 1224 - 1225.
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NEJMHome page
K. Bjoro, S. S. Froland, Z. Yun, H. H. Samdal, and T. Haaland
Hepatitis C Infection in Patients with Primary Hypogammaglobulinemia after Treatment with Contaminated Immune Globulin
N. Engl. J. Med., December 15, 1994; 331(24): 1607 - 1611.
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