Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Mar 28;92(7):2755–2759. doi: 10.1073/pnas.92.7.2755

Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant.

A Weiner 1, A L Erickson 1, J Kansopon 1, K Crawford 1, E Muchmore 1, A L Hughes 1, M Houghton 1, C M Walker 1
PMCID: PMC42297  PMID: 7708719

Abstract

Hepatitis C virus (HCV) establishes a persistent infection in humans and chimpanzees despite the presence of virus-specific, class I major histocompatibility complex-restricted CD8+ cytotoxic T lymphocytes (CTLs) in the liver. The data presented here demonstrate that CTLs directed against a conserved epitope in the HCV nonstructural 3 protein persist in the liver of a chronically infected chimpanzee for at least 2 years after infection. However, these CTLs did not recognize the HCV quasi-species present in the plasma of this animal at week 16 postinfection or at later time points. Escape from the CTL response was facilitated by an aspartic acid to glutamic acid (D-->E) substitution at amino acid position 1449 in all HCV genomes that were sequenced. The results of this study strongly support the concept that CTL responses can select for variant viruses with an enhanced ability to persist in a host and have important implications for the design of vaccines against HCV.

Full text

PDF
2755

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aebischer T., Moskophidis D., Rohrer U. H., Zinkernagel R. M., Hengartner H. In vitro selection of lymphocytic choriomeningitis virus escape mutants by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11047–11051. doi: 10.1073/pnas.88.24.11047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alter M. J., Margolis H. S., Krawczynski K., Judson F. N., Mares A., Alexander W. J., Hu P. Y., Miller J. K., Gerber M. A., Sampliner R. E. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med. 1992 Dec 31;327(27):1899–1905. doi: 10.1056/NEJM199212313272702. [DOI] [PubMed] [Google Scholar]
  3. Barber L. D., Parham P. Peptide binding to major histocompatibility complex molecules. Annu Rev Cell Biol. 1993;9:163–206. doi: 10.1146/annurev.cb.09.110193.001115. [DOI] [PubMed] [Google Scholar]
  4. Bertoletti A., Costanzo A., Chisari F. V., Levrero M., Artini M., Sette A., Penna A., Giuberti T., Fiaccadori F., Ferrari C. Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J Exp Med. 1994 Sep 1;180(3):933–943. doi: 10.1084/jem.180.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  6. Botarelli P., Brunetto M. R., Minutello M. A., Calvo P., Unutmaz D., Weiner A. J., Choo Q. L., Shuster J. R., Kuo G., Bonino F. T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology. 1993 Feb;104(2):580–587. doi: 10.1016/0016-5085(93)90430-k. [DOI] [PubMed] [Google Scholar]
  7. Bradley D. W., Krawczynski K., Ebert J. W., McCaustland K. A., Choo Q. L., Houghton M. A., Kuo G. Parenterally transmitted non-A, non-B hepatitis: virus-specific antibody response patterns in hepatitis C virus-infected chimpanzees. Gastroenterology. 1990 Oct;99(4):1054–1060. doi: 10.1016/0016-5085(90)90626-c. [DOI] [PubMed] [Google Scholar]
  8. Bradley D. W., Maynard J. E. Etiology and natural history of post-transfusion and enterically-transmitted non-A, non-B hepatitis. Semin Liver Dis. 1986 Feb;6(1):56–66. doi: 10.1055/s-2008-1040794. [DOI] [PubMed] [Google Scholar]
  9. Chen Z. W., Shen L., Miller M. D., Ghim S. H., Hughes A. L., Letvin N. L. Cytotoxic T lymphocytes do not appear to select for mutations in an immunodominant epitope of simian immunodeficiency virus gag. J Immunol. 1992 Dec 15;149(12):4060–4066. [PubMed] [Google Scholar]
  10. Chisari F. V., Ferrari C., Mondelli M. U. Hepatitis B virus structure and biology. Microb Pathog. 1989 May;6(5):311–325. doi: 10.1016/0882-4010(89)90073-9. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Choo Q. L., Weiner A. J., Overby L. R., Kuo G., Houghton M., Bradley D. W. Hepatitis C virus: the major causative agent of viral non-A, non-B hepatitis. Br Med Bull. 1990 Apr;46(2):423–441. doi: 10.1093/oxfordjournals.bmb.a072408. [DOI] [PubMed] [Google Scholar]
  13. Erickson A. L., Houghton M., Choo Q. L., Weiner A. J., Ralston R., Muchmore E., Walker C. M. Hepatitis C virus-specific CTL responses in the liver of chimpanzees with acute and chronic hepatitis C. J Immunol. 1993 Oct 15;151(8):4189–4199. [PubMed] [Google Scholar]
  14. Ferrari C., Valli A., Galati L., Penna A., Scaccaglia P., Giuberti T., Schianchi C., Missale G., Marin M. G., Fiaccadori F. T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections. Hepatology. 1994 Feb;19(2):286–295. [PubMed] [Google Scholar]
  15. Fu Y. X., Li W. H. Statistical tests of neutrality of mutations. Genetics. 1993 Mar;133(3):693–709. doi: 10.1093/genetics/133.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Horwitz M. S., Yanagi Y., Oldstone M. B. T-cell receptors from virus-specific cytotoxic T lymphocytes recognizing a single immunodominant nine-amino-acid viral epitope show marked diversity. J Virol. 1994 Jan;68(1):352–357. doi: 10.1128/jvi.68.1.352-357.1994. [DOI] [PMC free article] [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. Kita H., Moriyama T., Kaneko T., Harase I., Nomura M., Miura H., Nakamura I., Yazaki Y., Imawari M. HLA B44-restricted cytotoxic T lymphocytes recognizing an epitope on hepatitis C virus nucleocapsid protein. Hepatology. 1993 Nov;18(5):1039–1044. [PubMed] [Google Scholar]
  19. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  20. Koup R. A. Virus escape from CTL recognition. J Exp Med. 1994 Sep 1;180(3):779–782. doi: 10.1084/jem.180.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Koziel M. J., Dudley D., Afdhal N., Choo Q. L., Houghton M., Ralston R., Walker B. D. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV. J Virol. 1993 Dec;67(12):7522–7532. doi: 10.1128/jvi.67.12.7522-7532.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koziel M. J., Dudley D., Wong J. T., Dienstag J., Houghton M., Ralston R., Walker B. D. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol. 1992 Nov 15;149(10):3339–3344. [PubMed] [Google Scholar]
  23. 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]
  24. Martell M., Esteban J. I., Quer J., Vargas V., Esteban R., Guardia J., Gómez J. Dynamic behavior of hepatitis C virus quasispecies in patients undergoing orthotopic liver transplantation. J Virol. 1994 May;68(5):3425–3436. doi: 10.1128/jvi.68.5.3425-3436.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Messing J. New M13 vectors for cloning. Methods Enzymol. 1983;101:20–78. doi: 10.1016/0076-6879(83)01005-8. [DOI] [PubMed] [Google Scholar]
  26. Meyerhans A., Dadaglio G., Vartanian J. P., Langlade-Demoyen P., Frank R., Asjö B., Plata F., Wain-Hobson S. In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specific in vitro reactivity. Eur J Immunol. 1991 Oct;21(10):2637–2640. doi: 10.1002/eji.1830211051. [DOI] [PubMed] [Google Scholar]
  27. Minutello M. A., Pileri P., Unutmaz D., Censini S., Kuo G., Houghton M., Brunetto M. R., Bonino F., Abrignani S. Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J Exp Med. 1993 Jul 1;178(1):17–25. doi: 10.1084/jem.178.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Moor-Jankowski J., Mahoney C. J. Chimpanzees in captivity: humane handling and breeding within the confines imposed by medical research and testing. Position paper for the Jane Goodall Institute Workshop on Psychological Well-Being of Captive Chimpanzees 1st to 3rd December, 1987. J Med Primatol. 1989;18(1):1–26. doi: 10.1002/ajp.1350180102. [DOI] [PubMed] [Google Scholar]
  29. Ogata N., Alter H. J., Miller R. H., Purcell R. H. Nucleotide sequence and mutation rate of the H strain of hepatitis C virus. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3392–3396. doi: 10.1073/pnas.88.8.3392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Oldstone M. B. Viral persistence. Cell. 1989 Feb 24;56(4):517–520. doi: 10.1016/0092-8674(89)90573-4. [DOI] [PubMed] [Google Scholar]
  32. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  33. Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
  34. Shimizu Y. K., Hijikata M., Iwamoto A., Alter H. J., Purcell R. H., Yoshikura H. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses. J Virol. 1994 Mar;68(3):1494–1500. doi: 10.1128/jvi.68.3.1494-1500.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shimizu Y. K., Weiner A. J., Rosenblatt J., Wong D. C., Shapiro M., Popkin T., Houghton M., Alter H. J., Purcell R. H. Early events in hepatitis C virus infection of chimpanzees. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6441–6444. doi: 10.1073/pnas.87.16.6441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shirai M., Okada H., Nishioka M., Akatsuka T., Wychowski C., Houghten R., Pendleton C. D., Feinstone S. M., Berzofsky J. A. An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans. J Virol. 1994 May;68(5):3334–3342. doi: 10.1128/jvi.68.5.3334-3342.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Simmonds P., Holmes E. C., Cha T. A., Chan S. W., McOmish F., Irvine B., Beall E., Yap P. L., Kolberg J., Urdea M. S. 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 Nov;74(Pt 11):2391–2399. doi: 10.1099/0022-1317-74-11-2391. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. 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]
  40. Weiner A. J., Kuo G., Bradley D. W., Bonino F., Saracco G., Lee C., Rosenblatt J., Choo Q. L., Houghton M. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet. 1990 Jan 6;335(8680):1–3. doi: 10.1016/0140-6736(90)90134-q. [DOI] [PubMed] [Google Scholar]
  41. Zinkernagel R. M., Hengartner H. HIV. Games that viruses play. Nature. 1991 Dec 12;354(6353):433–434. doi: 10.1038/354433a0. [DOI] [PubMed] [Google Scholar]
  42. de Campos-Lima P. O., Gavioli R., Zhang Q. J., Wallace L. E., Dolcetti R., Rowe M., Rickinson A. B., Masucci M. G. HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population. Science. 1993 Apr 2;260(5104):98–100. doi: 10.1126/science.7682013. [DOI] [PubMed] [Google Scholar]
  43. de Campos-Lima P. O., Levitsky V., Brooks J., Lee S. P., Hu L. F., Rickinson A. B., Masucci M. G. T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues. J Exp Med. 1994 Apr 1;179(4):1297–1305. doi: 10.1084/jem.179.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES