Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Sep 15;98(6):1432–1440. doi: 10.1172/JCI118931

Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection.

B Rehermann 1, K M Chang 1, J G McHutchison 1, R Kokka 1, M Houghton 1, F V Chisari 1
PMCID: PMC507570  PMID: 8823309

Abstract

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.

Full Text

The Full Text of this article is available as a PDF (258.7 KB).

Selected References

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

  1. Battegay M., Fikes J., Di Bisceglie A. M., Wentworth P. A., Sette A., Celis E., Ching W. M., Grakoui A., Rice C. M., Kurokohchi K. 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 Apr;69(4):2462–2470. doi: 10.1128/jvi.69.4.2462-2470.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cerny A., Ferrari C., Chisari F. V. The class I-restricted cytotoxic T lymphocyte response to predetermined epitopes in the hepatitis B and C viruses. Curr Top Microbiol Immunol. 1994;189:169–186. doi: 10.1007/978-3-642-78530-6_10. [DOI] [PubMed] [Google Scholar]
  3. Cerny A., McHutchison J. G., Pasquinelli C., Brown M. E., Brothers M. A., Grabscheid B., Fowler P., Houghton M., Chisari F. V. Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif. J Clin Invest. 1995 Feb;95(2):521–530. doi: 10.1172/JCI117694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan S. W., McOmish F., Holmes E. C., Dow B., Peutherer J. F., Follett E., Yap P. L., Simmonds P. Analysis of a new hepatitis C virus type and its phylogenetic relationship to existing variants. J Gen Virol. 1992 May;73(Pt 5):1131–1141. doi: 10.1099/0022-1317-73-5-1131. [DOI] [PubMed] [Google Scholar]
  5. 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]
  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. 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]
  9. 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 Jan;4(1):25–36. doi: 10.1016/s1074-7613(00)80295-2. [DOI] [PubMed] [Google Scholar]
  10. Houghton M., Weiner A., Han J., Kuo G., Choo Q. L. Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease. Hepatology. 1991 Aug;14(2):381–388. [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Koziel M. J., Dudley D., Afdhal N., Grakoui A., Rice C. M., Choo Q. L., Houghton M., Walker B. D. HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release. J Clin Invest. 1995 Nov;96(5):2311–2321. doi: 10.1172/JCI118287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
  16. Mosmann T. R. Cytokine patterns during the progression to AIDS. Science. 1994 Jul 8;265(5169):193–194. doi: 10.1126/science.8023139. [DOI] [PubMed] [Google Scholar]
  17. Nishioka K., Watanabe J., Furuta S., Tanaka E., Iino S., Suzuki H., Tsuji T., Yano M., Kuo G., Choo Q. L. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer. 1991 Jan 15;67(2):429–433. doi: 10.1002/1097-0142(19910115)67:2<429::aid-cncr2820670218>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  18. Rehermann B., Lau D., Hoofnagle J. H., Chisari F. V. Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J Clin Invest. 1996 Apr 1;97(7):1655–1665. doi: 10.1172/JCI118592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe Y., Koi S., Onji M., Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6547–6549. doi: 10.1073/pnas.87.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shirai M., Arichi T., Nishioka M., Nomura T., Ikeda K., Kawanishi K., Engelhard V. H., Feinstone S. M., Berzofsky J. A. CTL responses of HLA-A2.1-transgenic mice specific for hepatitis C viral peptides predict epitopes for CTL of humans carrying HLA-A2.1. J Immunol. 1995 Mar 15;154(6):2733–2742. [PubMed] [Google Scholar]
  21. 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]
  22. Simmonds P. Variability of hepatitis C virus. Hepatology. 1995 Feb;21(2):570–583. doi: 10.1002/hep.1840210243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Stuyver L., Wyseur A., van Arnhem W., Lunel F., Laurent-Puig P., Pawlotsky J. M., Kleter B., Bassit L., Nkengasong J., van Doorn L. J. Hepatitis C virus genotyping by means of 5'-UR/core line probe assays and molecular analysis of untypeable samples. Virus Res. 1995 Oct;38(2-3):137–157. doi: 10.1016/0168-1702(95)00052-r. [DOI] [PubMed] [Google Scholar]
  24. Tsui L. V., Guidotti L. G., Ishikawa T., Chisari F. V. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12398–12402. doi: 10.1073/pnas.92.26.12398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vitiello A., Marchesini D., Furze J., Sherman L. A., Chesnut R. W. Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J Exp Med. 1991 Apr 1;173(4):1007–1015. doi: 10.1084/jem.173.4.1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Weiner A., Erickson A. L., Kansopon J., Crawford K., Muchmore E., Hughes A. L., Houghton M., Walker C. M. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2755–2759. doi: 10.1073/pnas.92.7.2755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wentworth P. A., Celis E., Crimi C., Stitely S., Hale L., Tsai V., Serra H. M., Del Guercio M. F., Livingston B., Alazard D. In vitro induction of primary, antigen-specific CTL from human peripheral blood mononuclear cells stimulated with synthetic peptides. Mol Immunol. 1995 Jun;32(9):603–612. doi: 10.1016/0161-5890(95)00037-f. [DOI] [PubMed] [Google Scholar]
  28. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES