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. 1995 Feb;69(2):773–778. doi: 10.1128/jvi.69.2.773-778.1995

Sequence evolution of the hypervariable region in the putative envelope region E2/NS1 of hepatitis C virus is correlated with specific humoral immune responses.

L J van Doorn 1, I Capriles 1, G Maertens 1, R DeLeys 1, K Murray 1, T Kos 1, H Schellekens 1, W Quint 1
PMCID: PMC188641  PMID: 7815542

Abstract

Sequence evolution of the hypervariable region 1 (HVR1) in the N terminus of E2/NS1 of hepatitis C virus (HCV) was studied retrospectively in six chimpanzees inoculated with the same genotype 1b strain, containing a unique predominant HVR1 sequence. Immediately after inoculation, all animals contained the same HVR predominant sequence. Two animals developed an acute self-limiting infection. Anti-HVR1 immunoglobulin G (IgG) was produced 40 to 60 days after inoculation and rapidly disappeared after normalization of transaminases. Another chimpanzee, previously infected with human immunodeficiency virus type 1, showed a delayed response to HVR1 epitopes after superinfection with HCV. No sequence variation of HVR1 was observed in these two animals during the transient viremia in the acute phase. Three other chimpanzees developed a chronic HCV infection. During follow up, sequence evolution occurred in two animals and their anti-HVR1 response remained at varying but detectable levels. The first mutations occurred immediately after the production of anti-HVR1 during the acute phase. However, IgM anti-HVR1 was not detectable. Remarkably, HVR1 sequences remained conserved for more than 6 years in another chronically infected animal. This correlated with the complete absence of detectable anti-HVR1 during this period. Seven years after inoculation, anti-HVR1 IgG was produced and coincided with an HVR1 alteration. These results strongly suggest the involvement of neutralizing anti-HVR antibodies in sequence evolution of HVR1 through immune selection.

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Selected References

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  1. Bukh J., Purcell R. H., Miller R. H. At least 12 genotypes of hepatitis C virus predicted by sequence analysis of the putative E1 gene of isolates collected worldwide. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8234–8238. doi: 10.1073/pnas.90.17.8234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chesebro B., Nishio J., Perryman S., Cann A., O'Brien W., Chen I. S., Wehrly K. Identification of human immunodeficiency virus envelope gene sequences influencing viral entry into CD4-positive HeLa cells, T-leukemia cells, and macrophages. J Virol. 1991 Nov;65(11):5782–5789. doi: 10.1128/jvi.65.11.5782-5789.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chesebro B., Wehrly K., Nishio J., Perryman S. Macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual V3 envelope sequence homogeneity in comparison with T-cell-tropic isolates: definition of critical amino acids involved in cell tropism. J Virol. 1992 Nov;66(11):6547–6554. doi: 10.1128/jvi.66.11.6547-6554.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Choo Q. L., Kuo G., Ralston R., Weiner A., Chien D., Van Nest G., Han J., Berger K., Thudium K., Kuo C. Vaccination of chimpanzees against infection by the hepatitis C virus. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1294–1298. doi: 10.1073/pnas.91.4.1294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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-borne non-A, non-B viral hepatitis genome. Science. 1989 Apr 21;244(4902):359–362. doi: 10.1126/science.2523562. [DOI] [PubMed] [Google Scholar]
  7. Choo Q. L., Richman K. H., Han J. H., Berger K., Lee C., Dong C., Gallegos C., Coit D., Medina-Selby R., Barr P. J. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2451–2455. doi: 10.1073/pnas.88.6.2451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Domingo E., Díez J., Martínez M. A., Hernández J., Holguín A., Borrego B., Mateu M. G. New observations on antigenic diversification of RNA viruses. Antigenic variation is not dependent on immune selection. J Gen Virol. 1993 Oct;74(Pt 10):2039–2045. doi: 10.1099/0022-1317-74-10-2039. [DOI] [PubMed] [Google Scholar]
  9. Enomoto N., Sakamoto N., Kurosaki M., Marumo F., Sato C. The hypervariable region of the HCV genome changes sequentially during the progression of acute HCV infection to chronic hepatitis. J Hepatol. 1993 Mar;17(3):415–416. doi: 10.1016/s0168-8278(05)80226-0. [DOI] [PubMed] [Google Scholar]
  10. Fouchier R. A., Groenink M., Kootstra N. A., Tersmette M., Huisman H. G., Miedema F., Schuitemaker H. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol. 1992 May;66(5):3183–3187. doi: 10.1128/jvi.66.5.3183-3187.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Giovannini M., Tagger A., Ribero M. L., Zuccotti G., Pogliani L., Grossi A., Ferroni P., Fiocchi A. Maternal-infant transmission of hepatitis C virus and HIV infections: a possible interaction. Lancet. 1990 May 12;335(8698):1166–1166. doi: 10.1016/0140-6736(90)91174-9. [DOI] [PubMed] [Google Scholar]
  12. Higashi Y., Kakumu S., Yoshioka K., Wakita T., Mizokami M., Ohba K., Ito Y., Ishikawa T., Takayanagi M., Nagai Y. Dynamics of genome change in the E2/NS1 region of hepatitis C virus in vivo. Virology. 1993 Dec;197(2):659–668. doi: 10.1006/viro.1993.1641. [DOI] [PubMed] [Google Scholar]
  13. Hijikata M., Kato N., Ootsuyama Y., Nakagawa M., Ohkoshi S., Shimotohno K. Hypervariable regions in the putative glycoprotein of hepatitis C virus. Biochem Biophys Res Commun. 1991 Feb 28;175(1):220–228. doi: 10.1016/s0006-291x(05)81223-9. [DOI] [PubMed] [Google Scholar]
  14. Hwang S. S., Boyle T. J., Lyerly H. K., Cullen B. R. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  15. Kato N., Ootsuyama Y., Ohkoshi S., Nakazawa T., Sekiya H., Hijikata M., Shimotohno K. Characterization of hypervariable regions in the putative envelope protein of hepatitis C virus. Biochem Biophys Res Commun. 1992 Nov 30;189(1):119–127. doi: 10.1016/0006-291x(92)91533-v. [DOI] [PubMed] [Google Scholar]
  16. Kato N., Ootsuyama Y., Tanaka T., Nakagawa M., Nakazawa T., Muraiso K., Ohkoshi S., Hijikata M., Shimotohno K. Marked sequence diversity in the putative envelope proteins of hepatitis C viruses. Virus Res. 1992 Feb;22(2):107–123. doi: 10.1016/0168-1702(92)90038-b. [DOI] [PubMed] [Google Scholar]
  17. Kato N., Sekiya H., Ootsuyama Y., Nakazawa T., Hijikata M., Ohkoshi S., Shimotohno K. Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus. J Virol. 1993 Jul;67(7):3923–3930. doi: 10.1128/jvi.67.7.3923-3930.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lesniewski R. R., Boardway K. M., Casey J. M., Desai S. M., Devare S. G., Leung T. K., Mushahwar I. K. Hypervariable 5'-terminus of hepatitis C virus E2/NS1 encodes antigenically distinct variants. J Med Virol. 1993 Jun;40(2):150–156. doi: 10.1002/jmv.1890400213. [DOI] [PubMed] [Google Scholar]
  19. Martell M., Esteban J. I., Quer J., Genescà J., Weiner A., Esteban R., Guardia J., Gómez J. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J Virol. 1992 May;66(5):3225–3229. doi: 10.1128/jvi.66.5.3225-3229.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Okada S., Akahane Y., Suzuki H., Okamoto H., Mishiro S. The degree of variability in the amino terminal region of the E2/NS1 protein of hepatitis C virus correlates with responsiveness to interferon therapy in viremic patients. Hepatology. 1992 Sep;16(3):619–624. doi: 10.1002/hep.1840160302. [DOI] [PubMed] [Google Scholar]
  21. Okamoto H., Kojima M., Okada S., Yoshizawa H., Iizuka H., Tanaka T., Muchmore E. E., Peterson D. A., Ito Y., Mishiro S. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology. 1992 Oct;190(2):894–899. doi: 10.1016/0042-6822(92)90933-g. [DOI] [PubMed] [Google Scholar]
  22. Sekiya H., Kato N., Ootsuyama Y., Nakazawa T., Yamauchi K., Shimotohno K. Genetic alterations of the putative envelope proteins encoding region of the hepatitis C virus in the progression to relapsed phase from acute hepatitis: humoral immune response to hypervariable region 1. Int J Cancer. 1994 Jun 1;57(5):664–670. doi: 10.1002/ijc.2910570509. [DOI] [PubMed] [Google Scholar]
  23. Simmonds P., Alberti A., Alter H. J., Bonino F., Bradley D. W., Brechot C., Brouwer J. T., Chan S. W., Chayama K., Chen D. S. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology. 1994 May;19(5):1321–1324. [PubMed] [Google Scholar]
  24. Stuyver L., van Arnhem W., Wyseur A., Hernandez F., Delaporte E., Maertens G. Classification of hepatitis C viruses based on phylogenetic analysis of the envelope 1 and nonstructural 5B regions and identification of five additional subtypes. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10134–10138. doi: 10.1073/pnas.91.21.10134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Taniguchi S., Okamoto H., Sakamoto M., Kojima M., Tsuda F., Tanaka T., Munekata E., Muchmore E. E., Peterson D. A., Mishiro S. 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 Jul;195(1):297–301. doi: 10.1006/viro.1993.1378. [DOI] [PubMed] [Google Scholar]
  26. Tsiquaye K. N., Bird R. G., Tovey G., Wyke R. J., Williams R., Zuckerman A. J. Further evidence of cellular changes associated with non-A, non-B hepatitis. J Med Virol. 1980;5(1):63–71. doi: 10.1002/jmv.1890050108. [DOI] [PubMed] [Google Scholar]
  27. Weiner A. J., Brauer M. J., Rosenblatt J., Richman K. H., Tung J., Crawford K., Bonino F., Saracco G., Choo Q. L., Houghton M. Variable and hypervariable domains are found in the regions of HCV corresponding to the flavivirus envelope and NS1 proteins and the pestivirus envelope glycoproteins. Virology. 1991 Feb;180(2):842–848. doi: 10.1016/0042-6822(91)90104-j. [DOI] [PubMed] [Google Scholar]
  28. Weiner A. J., Christopherson C., Hall J. E., Bonino F., Saracco G., Brunetto M. R., Crawford K., Marion C. D., Crawford K. A., Venkatakrishna S. Sequence variation in hepatitis C viral isolates. J Hepatol. 1991;13 (Suppl 4):S6–14. doi: 10.1016/0168-8278(91)90015-4. [DOI] [PubMed] [Google Scholar]
  29. Weiner A. J., Geysen H. M., Christopherson C., Hall J. E., Mason T. J., Saracco G., Bonino F., Crawford K., Marion C. D., Crawford K. A. Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3468–3472. doi: 10.1073/pnas.89.8.3468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weiner A. J., Thaler M. M., Crawford K., Ching K., Kansopon J., Chien D. Y., Hall J. E., Hu F., Houghton M. A unique, predominant hepatitis C virus variant found in an infant born to a mother with multiple variants. J Virol. 1993 Jul;67(7):4365–4368. doi: 10.1128/jvi.67.7.4365-4368.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhang L. Q., MacKenzie P., Cleland A., Holmes E. C., Brown A. J., Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol. 1993 Jun;67(6):3345–3356. doi: 10.1128/jvi.67.6.3345-3356.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. van Doorn L. J., Quint W., Tsiquaye K., Voermans J., Paelinck D., Kos T., Maertens G., Schellekens H., Murray K. Longitudinal analysis of hepatitis C virus infection and genetic drift of the hypervariable region. J Infect Dis. 1994 Jun;169(6):1226–1235. doi: 10.1093/infdis/169.6.1226. [DOI] [PubMed] [Google Scholar]

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