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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Apr 1;97(7):1655–1665. doi: 10.1172/JCI118592

Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.

B Rehermann 1, D Lau 1, J H Hoofnagle 1, F V Chisari 1
PMCID: PMC507230  PMID: 8601631

Abstract

Clearance of the hepatitis B virus (HBV) during acute hepatitis is associated with a strong, polyclonal, multispecific cytotoxic T lymphocyte (CTL) response to the viral envelope, nucleocapsid and polymerase proteins that persists for decades after clinical recovery. In contrast, chronically infected patients usually fail to mount a strong CTL response to this virus. In this study we demonstrate that chronically infected patients who experience a spontaneous or interferon-induced remission develop a CTL response to HBV that is similar in strength and specificity to patients who have recovered from acute hepatitis. The results suggest that specific immunotherapeutic enhancement of the CTL response to HBV should be possible in chronically infected patients, and that it could lead to viral clearance in these individuals with resolution of chronic liver disease.

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Selected References

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  1. Alexander G. J., Brahm J., Fagan E. A., Smith H. M., Daniels H. M., Eddleston A. L., Williams R. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet. 1987 Jul 11;2(8550):66–69. doi: 10.1016/s0140-6736(87)92735-8. [DOI] [PubMed] [Google Scholar]
  2. Barnaba V., Franco A., Alberti A., Balsano C., Benvenuto R., Balsano F. Recognition of hepatitis B virus envelope proteins by liver-infiltrating T lymphocytes in chronic HBV infection. J Immunol. 1989 Oct 15;143(8):2650–2655. [PubMed] [Google Scholar]
  3. Bertoletti A., Ferrari C., Fiaccadori F., Penna A., Margolskee R., Schlicht H. J., Fowler P., Guilhot S., Chisari F. V. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10445–10449. doi: 10.1073/pnas.88.23.10445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonino F., Hoyer B., Nelson J., Engle R., Verme G., Gerin J. Hepatitis B virus DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver. Hepatology. 1981 Sep-Oct;1(5):386–391. doi: 10.1002/hep.1840010503. [DOI] [PubMed] [Google Scholar]
  5. Bonino F., Rosina F., Rizzetto M., Rizzi R., Chiaberge E., Tardanico R., Callea F., Verme G. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology. 1986 May;90(5 Pt 1):1268–1273. doi: 10.1016/0016-5085(86)90395-1. [DOI] [PubMed] [Google Scholar]
  6. Cerny A., Fowler P., Brothers M. A., Houghton M., Schlicht H. J., Chisari F. V. Induction in vitro of a primary human antiviral cytotoxic T cell response. Eur J Immunol. 1995 Feb;25(2):627–630. doi: 10.1002/eji.1830250248. [DOI] [PubMed] [Google Scholar]
  7. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Di Bisceglie A. M., Fong T. L., Fried M. W., Swain M. G., Baker B., Korenman J., Bergasa N. V., Waggoner J. G., Park Y., Hoofnagle J. H. A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B. Am J Gastroenterol. 1993 Nov;88(11):1887–1892. [PubMed] [Google Scholar]
  9. Fazekas de St Groth The evaluation of limiting dilution assays. J Immunol Methods. 1982 Mar 12;49(2):R11–R23. doi: 10.1016/0022-1759(82)90269-1. [DOI] [PubMed] [Google Scholar]
  10. Ferrari C., Penna A., Giuberti T., Tong M. J., Ribera E., Fiaccadori F., Chisari F. V. Intrahepatic, nucleocapsid antigen-specific T cells in chronic active hepatitis B. J Immunol. 1987 Sep 15;139(6):2050–2058. [PubMed] [Google Scholar]
  11. Guilhot S., Fowler P., Portillo G., Margolskee R. F., Ferrari C., Bertoletti A., Chisari F. V. Hepatitis B virus (HBV)-specific cytotoxic T-cell response in humans: production of target cells by stable expression of HBV-encoded proteins in immortalized human B-cell lines. J Virol. 1992 May;66(5):2670–2678. doi: 10.1128/jvi.66.5.2670-2678.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hoofnagle J. H., Peters M., Mullen K. D., Jones D. B., Rustgi V., Di Bisceglie A., Hallahan C., Park Y., Meschievitz C., Jones E. A. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology. 1988 Nov;95(5):1318–1325. doi: 10.1016/0016-5085(88)90367-8. [DOI] [PubMed] [Google Scholar]
  13. Jung M. C., Diepolder H. M., Spengler U., Wierenga E. A., Zachoval R., Hoffmann R. M., Eichenlaub D., Frösner G., Will H., Pape G. R. Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection. J Virol. 1995 Jun;69(6):3358–3368. doi: 10.1128/jvi.69.6.3358-3368.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Korenman J., Baker B., Waggoner J., Everhart J. E., Di Bisceglie A. M., Hoofnagle J. H. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med. 1991 Apr 15;114(8):629–634. doi: 10.7326/0003-4819-114-8-629. [DOI] [PubMed] [Google Scholar]
  15. Michalak T. I., Pasquinelli C., Guilhot S., Chisari F. V. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest. 1994 Jan;93(1):230–239. doi: 10.1172/JCI116950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Missale G., Redeker A., Person J., Fowler P., Guilhot S., Schlicht H. J., Ferrari C., Chisari F. V. HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J Exp Med. 1993 Mar 1;177(3):751–762. doi: 10.1084/jem.177.3.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nayersina R., Fowler P., Guilhot S., Missale G., Cerny A., Schlicht H. J., Vitiello A., Chesnut R., Person J. L., Redeker A. G. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol. 1993 May 15;150(10):4659–4671. [PubMed] [Google Scholar]
  18. Nayersina R., Fowler P., Guilhot S., Missale G., Cerny A., Schlicht H. J., Vitiello A., Chesnut R., Person J. L., Redeker A. G. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol. 1993 May 15;150(10):4659–4671. [PubMed] [Google Scholar]
  19. Pasek M., Goto T., Gilbert W., Zink B., Schaller H., MacKay P., Leadbetter G., Murray K. Hepatitis B virus genes and their expression in E. coli. Nature. 1979 Dec 6;282(5739):575–579. doi: 10.1038/282575a0. [DOI] [PubMed] [Google Scholar]
  20. Penna A., Chisari F. V., Bertoletti A., Missale G., Fowler P., Giuberti T., Fiaccadori F., Ferrari C. Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen. J Exp Med. 1991 Dec 1;174(6):1565–1570. doi: 10.1084/jem.174.6.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rehermann B., Fowler P., Sidney J., Person J., Redeker A., Brown M., Moss B., Sette A., Chisari F. V. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J Exp Med. 1995 Mar 1;181(3):1047–1058. doi: 10.1084/jem.181.3.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Schlicht H. J., Schaller H. The secretory core protein of human hepatitis B virus is expressed on the cell surface. J Virol. 1989 Dec;63(12):5399–5404. doi: 10.1128/jvi.63.12.5399-5404.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Scotto J., Hadchouel M., Hery C., Yvart J., Tiollais P., Brechot C. Detection of hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology. 1983 May-Jun;3(3):279–284. doi: 10.1002/hep.1840030301. [DOI] [PubMed] [Google Scholar]
  24. Takano S., Yokosuka O., Imazeki F., Tagawa M., Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology. 1995 Mar;21(3):650–655. [PubMed] [Google Scholar]
  25. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  26. Tsai S. L., Chen P. J., Lai M. Y., Yang P. M., Sung J. L., Huang J. H., Hwang L. H., Chang T. H., Chen D. S. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest. 1992 Jan;89(1):87–96. doi: 10.1172/JCI115590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Vitiello A., Ishioka G., Grey H. M., Rose R., Farness P., LaFond R., Yuan L., Chisari F. V., Furze J., Bartholomeuz R. Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans. J Clin Invest. 1995 Jan;95(1):341–349. doi: 10.1172/JCI117662. [DOI] [PMC free article] [PubMed] [Google Scholar]

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