Nature Medicine
2, 1104 - 1108 (1996)
doi:10.1038/nm1096-1104
The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T−lymphocyte responseBarbara Rehermann1, 3, Carlo Ferrari2, Claudio Pasquinelli1
& Francis V. Chisari1, 4
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, SBR-10, 10666 North Torrey Pines Road, La Jolla, California 92037, USA
2Cattedra Malattie Infettive, Università di Parma and Divisione Malattie Infettive, Azienda Ospedaliera di Parma, 43100 Parma, Italy
3B.R. present address: Abteilung Gastroenterologie und Hepatologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany
4Correspondence should be addressed to F.V.C. It is widely believed that the hepatitis B virus (HBV) is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes (CTLs) during acute viral hepatitis. We now demonstrate that traces of HBV are often detectable in the blood for many years after clinical recovery from acute hepatitis, despite the presence of serum antibodies and HBV−specific CTLs, which can be present at acute−stage levels. The strength of the CTL response to HBV following clinical recovery correlates with persistence of HBV DNA. It is of particular interest that HBV−specific CTLs from patients studied up to 23 years after clinical and serological recovery expressed activation markers (HLA−DR, CD69) indicating recent contact with antigen. These results suggest that sterilizing immunity to HBV frequently fails to occur after recovery from acute hepatitis and that traces of virus can maintain the CTL response for decades following clinical recovery, apparently creating a negative feedback loop that keeps the virus under control, perhaps for life.
REFERENCES
- Penna, A. et al. Cytotoxic T lymphocytes recognize an HLA-A2 restricted epitope within the hepatitis B virus nucleocapsid antigen. J. Exp. Med. 174, 1565−1570 (1991). | PubMed | ISI | ChemPort |
- Bertoletti, A. et al. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc. Natl Acad. Sci USA 88, 10445−10449 (1991). | PubMed | ChemPort |
- Missale, G. et al. HLA-A31 and Aw68 restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J. Exp. Med. 177, 751−762 (1993). | PubMed | ISI | ChemPort |
- Rehermann, B. et al. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J. Exp. Med. 181, 1047−1058 (1995). | PubMed | ISI | ChemPort |
- Michalak, T.I., Pasquinelli, C., Guilhot, S. & Chisari, F.V. Hepatitis B virus persistence after recovery from acute viral hepatitis. J. Clin. Invest. 93, 230−239 (1994). | PubMed | ISI | ChemPort |
- Rehermann, B., Lau, D., Hoofnagle, J. & Chisari, F.V. Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J. Clin. Invest. 97, 1655−1665 (1996). | PubMed | ISI | ChemPort |
- Nayersina, R. et al. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J. Immunol. 150, 4659−4671 (1993). | PubMed | ISI | ChemPort |
- Scotto, J. et al. Detection of hepatitis B virus DNA in serum by a simple spot hybridization technique: Comparison with results for other viral markers. Hepatology 3, 279−284 (1983). | PubMed | ISI | ChemPort |
- Bonino, F. et al. Hepatitis B virus DNA in the sera of HBs Ag carriers: A marker of active hepatitis B virus replication in the liver. Hepatology 1, 386−391 (1981). | PubMed | ISI | ChemPort |
- Mandel, T.E., Phipps, R.P., Abbot, A. & Tew, J.G. The follicular dendritic cell: Long term antigen retention during immunity. Immunol. Rev. 53, 29−57 (1980). | PubMed | ISI | ChemPort |
- Tew, J.G., Kosko, M.H., Burton, G.F. & Szakal, A.K. Follicular dendritic cells as accessory cells. Immunol. Rev. 117, 185−211 (1990). | PubMed | ISI | ChemPort |
- Sprent, J. T and B memory cells. Cell 76, 315−322 (1994). | Article | PubMed | ISI | ChemPort |
- Lau, L.L., Jamieson, B.D., Somasundaram, T. & Ahmed, R. Cytotoxic T cell memory without antigen. Nature 369, 648−652 (1994). | Article | PubMed | ISI | ChemPort |
- Oehen, S., Waldner, H.P., Kündig, T., Hengartner, H. & Zinkernagel, R.M. Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen. J. Exp. Med. 176, 1273−1281 (1992). | PubMed | ISI | ChemPort |
- Muellbacher, A. The long-term maintenance of cytotoxic T cell memory does not require persistence of antigen. J. Exp. Med. 179, 317−321 (1994). | PubMed | ISI | ChemPort |
- Hou, S., Hyland, L., Ryan, K.W., Portner, A. & Doherty, P.C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652−654 (1994). | Article | PubMed | ISI | ChemPort |
- Demkowicz, W.E.Jr., Littaua, R.A., Wang, J. & Ennis, F.A. Human cytotoxic T-cell memory: Long-lived responses to vaccinia virus. J. Virol. 70, 2627−2631 (1996). | PubMed | ISI | ChemPort |
- Martin, B.A., Rowe, J.M., Kouides, P.A. & DiPersio, J.F. Hepatitis B reactivation following allogeneic bone marrow transplantation: Case report and review of the literature. Bone Marrow Transplant. 15, 145−148 (1995). | PubMed | ISI | ChemPort |
- Mclvor, C. et al. Fatal reactivation of precore mutant hepatitis B virus associated with fibrosing cholestatic hepatitis after bone marrow transplantation. Ann. Intern. Med. 121, 274−276 (1994). | PubMed |
- Chazouilleres, O. et al. "Occult" hepatitis B virus as source of infection in liver transplant recipients. Lancet 343, 142−146 (1994). | Article | PubMed | ISI | ChemPort |
- Preisler-Adams, S., Schlayer, H.-J., Peters, T., Hettler, F., Gerok, W. & Rasenack, J. Identification and sequence analysis of hepatitis B virus DNA in immunologically-negative infection. Arch. Virol. 133, 385−396 (1993). | PubMed | ChemPort |
- Thiers, V. et al. Transmission of hepatitis B from hepatitis B-seronegative subjects. Lancet ii, 1273−1276 (1988). | Article |
- Wachs, M.E. et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. Transplantation 59, 230−234 (1995). | PubMed | ISI | ChemPort |
- Pasek, M. et al. Hepatitis B virus genes and their expression in E. coli. Nature 282, 575−579 (1979). | PubMed | ISI | ChemPort |
- Chakrabarti, S., Brechling, K. & Moss, B. Vaccinia virus expression vector: Coexpression of beta-galactosidase provides visual screening of recombinant plaques. Mol. Cell. Biol. 5, 3403−3409 (1985). | PubMed | ISI | ChemPort |
- Schlicht, H.J. & Schaller, H. The secretory core protein of human hepatitis B virus is expressed on the cell surface. J. Virol. 63, 5399−5404 (1989). | PubMed | ISI | ChemPort |
- Guilhot, S. et al. Hepatitis B virus (HBV) specific cytolytic T cell response in humans: Production of target cells by stable expression of HBV-encoded proteins in immortalized human B cell lines. J. Virol. 66, 2670−2678 (1992). | PubMed | ISI | ChemPort |
- Fazekas, S. & Groth, S.T. The evaluation of limiting dilution assays. J. Immunol. Methods 49, R11−R23 (1982). | Article | PubMed |
- Madsen, M. & Johnson, H.E. A methodological study of E-rosette formation using AET-treated sheep erythrocytes. J. Immunol. Methods 27, 61−74 (1979). | Article | PubMed | ISI | ChemPort |
- Gilles, P.N., Fey, G. & Chisari, F.V. Tumor necrosis factor-alpha negatively regulates hepatitis B virus gene expression in transgenic mice. J. Virol. 66, 3955−3960 (1992). | PubMed | ISI | ChemPort |
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