Research Article| Volume 30, ISSUE 2, P177-184, February 1999

Immunodominant B-cell domains of hepatitis C virus envelope proteins E1 and E2 identified during early and late time points of infection


      Background/Aims: We characterized immunoreactive B-cell domains of hepatitis C virus (HCV) envelope proteins E1 and E2 by a peptide ELISA using sera of patients who were infected by the same isolate of HCV (HCV-AD78).
      Methods: Fifty-four overlapping peptides which corresponded to the sequence of E1 and E2 of isolate HCV-AD78 were used to detect specific antibodies. Three groups of HCV-AD78 related sera were analyzed. Two groups were from sera obtained at early time points of infection (months 4–15) from patients who later resolved infection (group A), or who later developed chronic disease (group B). Group C sera were from later time points of chronic disease. As a control, sera of chronic HCV patients who did not have HCV-AD78 infection were also analyzed (group D).
      Results: In group A, 25 of the 54 peptides produced OD405 above the cut-off, whereas 17 peptides produced such values in group B. Only 10 and 3 peptides yielded such values in groups C and D, respectively. The overall prevalence of antibodies against peptides was high in the early phase of infection (means of 28.7±14.8% and 25.9±14.5% in groups A and B, respectively). At later time points of chronic infection (group C), the overall prevalence was lower (mean 18.6±15.4%). Group D sera produced the lowest overall prevalence (mean 13.2±14.1%). Three peptides, covering aa271–290, aa481–500 and aa551–570, were recognized significantly more frequently (p<0.05) by group A sera than group B sera.
      Conclusions: We conclude that more linear epitopes of the HCV envelope are recognized with a high prevalence of antibodies, as was suggested previously. However, most B-cell domains of the HCV envelope induce a similarly high antibody response in patients who resolve infection or develop chronic disease.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Choo Q-L
        • Kuo G
        • Weiner AJ
        • Overby LR
        • Bradley DW
        • Houghton M
        Isolation of a cDNA clone derived from a blood-borne non-A, non-B hepatitis genome.
        Science. 1989; 244: 359-362
        • Alter HJ
        The chronic consequences of non-A, non-B hepatitis.
        in: Seeff LB Lewis JH Current Perspectives in Hepatology. Plenum, New York1989: 83-97
        • Simmonds P
        • Holmes EC
        • Cha T-A
        • Chan S-W
        • McOmish F
        • Irvine B
        • et al.
        Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region.
        J Gen Virol. 1993; 74: 2391-2399
        • Martell M
        • Esteban JI
        • Quer J
        • Genesca J
        • Weiner A
        • Esteban R
        • et al.
        Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution.
        J Virol. 1992; 66: 3225-3229
        • Kato N
        • Ootsuyama Y
        • Sekiya H
        • Ohkoshi S
        • Nakazawa T
        • Hijikata M
        • et al.
        Genetic drift in hypervariable region 1 of the viral genome in persistent hepatitis C virus infection.
        J Virol. 1994; 68: 4776-4784
        • Taniguchi S
        • Okamoto H
        • Sakamoto M
        • Kojima M
        • Tsuda F
        • Tanaka T
        • et al.
        A structurally flexible and antigenically variable N-terminal domain of the hepatitis C virus E2/NS1 protein: implication for an escape from antibody.
        Virology. 1993; 195: 297-301
        • Weiner AJ
        • Geysen HM
        • Christopherson C
        • Hall JE
        • Mason TJ
        • Saracco G
        • et al.
        Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections.
        PNAS. 1992; 89: 3468-3472
        • Choo Q-L
        • Kuo G
        • Ralston R
        • Weiner AJ
        • Chien D
        • van Nest G
        • et al.
        Vaccination of chimpanzees against infection by hepatitis C virus.
        PNAS. 1994; 91: 1294-1298
        • Rosa D
        • Campagnoli S
        • Moretto C
        • Guenzi E
        • Cousens L
        • Chin M
        • et al.
        A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.
        PNAS. 1996; 93: 1759-1763
        • Chien DY
        • Choo QL
        • Ralston R
        • Spaete R
        • Tong M
        • Houghton M
        • et al.
        Persistence of HCV despite antibodies to both putative envelope glycoproteins.
        Lancet. 1993; 342: 435-436
        • Höhne M
        • Schreier E
        • Roggendorf M
        Sequence variability in the env-coding region of hepatitis C virus isolated from patients infected during a single source outbreak.
        Arch Virol. 1994; 137: 25-34
        • Zibert A
        • Schreier E
        • Roggendorf M
        Antibodies in human sera specific to hypervariable region 1 of hepatitis C virus can block viral attachment.
        Virology. 1995; 208: 653-661
        • Zibert A
        • Kraas W
        • Meisel H
        • Jung G
        • Roggendorf M
        Epitope mapping of antibodies directed against hypervariable region 1 in acute self-limiting and chronic infections due to hepatitis C virus.
        J Virol. 1997; 71: 4123-4127
        • Farci P
        • Shimoda A
        • Wong D
        • Cabezon T
        • DeGiovannis D
        • Strazzera A
        • et al.
        Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against hypervariable region 1 of the envelope 2 protein.
        PNAS. 1996; 93: 15394-15399
        • Zibert A
        • Meisel H
        • Kraas W
        • Schulz A
        • Jung G
        • Roggendorf M
        Early antibody response against hypervariable region 1 is associated with acute self-limiting infection of hepatitis C virus.
        Hepatology. 1997; 25: 1245-1249
        • Meisel H
        • Reip A
        • Faltus B
        • Lu M
        • Porst H
        • Wiese M
        • et al.
        Transmission of hepatitis C virus to children and husbands by women infected with contaminated anti-D immunoglobulin.
        Lancet. 1995; 345 ([see comments]): 1209-1211
        • Kato N
        • Hijikata M
        • Ootsuyama Y
        • Nakagawa M
        • Ohkoshi S
        • Shimotohno K
        Genetic organization and diversity of the hepatitis C virus.
        Proc Natl Acad Sci USA. 1991; 88: 2451-2455
        • Lechner S
        • Rispeter K
        • Meisel H
        • Kraas W
        • Jung G
        • Roggendorf M
        • et al.
        Antibodies directed to envelope proteins of hepatitis C virus outside of hypervariable region 1.
        Virology. 1998; 243: 313-321
        • Zhang ZX
        • Sonnerborg A
        • Sallberg M
        Antigenic structure of the hepatitis C virus envelope 2 protein.
        Clin Exp Immunol. 1994; 98: 382-387
        • Ray R
        • Khanna A
        • Lagging LM
        • Meyer K
        • Choo QL
        • Ralston R
        • et al.
        Peptide immunogen mimicry of putative E1 glycoprotein-specific epitopes in hepatitis C virus.
        J Virol. 1994; 68 ([published erratum appears in J Virol 1994 Sep; 68(9): 6136]): 4420-4426
        • Pirisi M
        • Ferroni P
        • Fabris C
        • Toniutto P
        • Soardo G
        • Vitulli D
        • et al.
        Anti-envelope antibodies in anti-hepatitis C virus (HCV) positive patients with and without liver disease.
        Infection. 1995; 23: 24-28
        • Wang YF
        • Brotman B
        • Andrus L
        • Prince AM
        Immune response to epitopes of hepatitis C virus (HCV) structural proteins in HCV-infected humans and chimpanzees.
        J Infect Dis. 1996; 173: 808-821
        • Ching WM
        • Wychowski C
        • Beach MJ
        • Wang H
        • Davies CL
        • Carl M
        • et al.
        Interaction of immune sera with synthetic peptides corresponding to the structural protein region of hepatitis C virus.
        Proc Natl Acad Sci USA. 1992; 89: 3190-3194
        • Mink MA
        • Benichou S
        • Madaule P
        • Tiollais P
        • Prince AM
        • Inchauspe G
        Characterization and mapping of a B-cell immunogenic domain in hepatitis C virus E2 glycoprotein using a yeast peptide library.
        Virology. 1994; 200: 246-255
        • Chan SW
        • Bye JM
        • Jackson P
        • Allain JP
        Human recombinant antibodies specific for hepatitis C virus core and envelope E2 peptides from an immune phage display library.
        J Gen Virol. 1996; 77: 2531-2539
        • Kurosaki M
        • Enomoto N
        • Marumo F
        • Sato C
        Evolution and selection of hepatitis C virus variants in patients with chronic hepatitis.
        Virology. 1994; 205: 161-169
        • Higashi Y
        • Kakumu S
        • Yoshioka K
        • Wakita T
        • Mizokami M
        • Ohba K
        • et al.
        Dynamics of genome change in the E2/NS1 region of hepatitis C virus in vivo.
        Virology. 1993; 197: 659-668
        • Erickson AL
        • Houghton M
        • Choo QL
        • Weiner AJ
        • Ralston R
        • Muchmore E
        • et al.
        Hepatitis C virus-specific CTL responses in the liver of chimpanzees with acute and chronic hepatitis C.
        J Immunol. 1993; 151: 4189-4199
        • Battegay M
        • Fikes J
        • Di BA
        • Wentworth PA
        • Sette A
        • Celis E
        • et al.
        Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules.
        J Virol. 1995; 69: 2462-2470
        • Diepolder HM
        • Zachoval R
        • Hoffmann RM
        • Wierenga EA
        • Santantonio T
        • Jung MC
        • et al.
        Possible mechanism involving Tlymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.
        Lancer. 1995; 346: 1006-1007
        • Weiner A
        • Erickson AL
        • Kansopon J
        • Crawford K
        • Muchmore E
        • Hughes AL
        • et al.
        Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant.
        Proc Natl Acad Sci USA. 1995; 92: 2755-2759
        • Koziel MJ
        • Dudley D
        • Wong JT
        • Dienstag J
        • Houghton M
        • Ralston R
        • et al.
        Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis.
        J Immunol. 1992; 149: 3339-3344
        • LerouxRoels G
        • Esquivel CA
        • Deleys R
        • Stuyver L
        • Elewaut A
        • Philippe J
        • et al.
        Lymphoproliferative responses to hepatitis C virus core, E1, E2, and NS3 in patients with chronic hepatitis C infection treated with interferon alfa.
        Hepatology. 1996; 23: 8-16
        • Farci P
        • Alter HJ
        • Wong DC
        • Miller RH
        • Govindarajan S
        • Engle R
        • et al.
        Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization.
        PNAS. 1994; 91: 7792-7796
        • Shimizu YK
        • Hijikata M
        • Iwamoto A
        • Alter HJ
        • Purcell RH
        • Yoshikura H
        Neutralizing autibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses.
        J Virol. 1994; 68: 1494-1500
        • Lai ME
        • Mazzoleni AP
        • Argiolu F
        • De Virgilis S
        • Balestrieri A
        • Purcell RH
        • et al.
        Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children.
        Lancet. 1994; 343: 388-390
        • Laskus T
        • Wang LF
        • Rakela J
        • Vargas H
        • Pinna AD
        • Tsamandas AC
        • et al.
        Dynamic behavior of hepatitis C virus in chronically infected patients receiving liver graft from infected donors.
        Virology. 1996; 220: 171-176
        • Thomssen R
        • Bonk S
        • Thiele A
        Density heterogeneities of hepatitis C virus in human sera due to the binding of beta-lipoproteins and immunoglobulins.
        Med Microbiol Immunol Berl. 1993; 182: 329-334
        • Hijikata M
        • Shimizu YK
        • Kato H
        • Iwamoto A
        • Shih JW
        • Alter HJ
        • et al.
        Equilibrium centrifugation studies of hepatitis C virus: evidence for circulating immune complexes.
        J Virol. 1993; 67: 1953-1958