Journal of Experimental Medicine, Vol 181, 1047-1058, Copyright © 1995 by Rockefeller University Press

ARTICLES

The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis

B Rehermann, P Fowler, J Sidney, J Person, A Redeker, M Brown, B Moss, A Sette and FV Chisari
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla 92037.

Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Guy, C. S., Mulrooney-Cousins, P. M., Churchill, N. D., Michalak, T. I. (2008). Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus. J. Virol. 82: 8579-8591 [Abstract] [Full Text]  
• Mulrooney-Cousins, P. M., Michalak, T. I. (2008). Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity. J. Virol. 82: 7540-7550 [Abstract] [Full Text]  
• Stoffels, R. J., Spencer, H. G. (2008). An Asymmetric Model of Heterozygote Advantage at Major Histocompatibility Complex Genes: Degenerate Pathogen Recognition and Intersection Advantage. Genetics 178: 1473-1489 [Abstract] [Full Text]  
• Bryant, K. F., Coen, D. M. (2008). Inhibition of Translation by a Short Element in the 5' Leader of the Herpes Simplex Virus 1 DNA Polymerase Transcript. J. Virol. 82: 77-85 [Abstract] [Full Text]  
• Depla, E., Van der Aa, A., Livingston, B. D., Crimi, C., Allosery, K., De Brabandere, V., Krakover, J., Murthy, S., Huang, M., Power, S., Babe, L., Dahlberg, C., McKinney, D., Sette, A., Southwood, S., Philip, R., Newman, M. J., Meheus, L. (2008). Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections. J. Virol. 82: 435-450 [Abstract] [Full Text]  
• Dusheiko, G, Antonakopoulos, N (2008). Current treatment of hepatitis B. Gut 57: 105-124 [Full Text]  
• Frank, I., Budde, C., Fiedler, M., Dahmen, U., Viazov, S., Lu, M., Dittmer, U., Roggendorf, M. (2007). Acute Resolving Woodchuck Hepatitis Virus (WHV) Infection Is Associated with a Strong Cytotoxic T-Lymphocyte Response to a Single WHV Core Peptide. J. Virol. 81: 7156-7163 [Abstract] [Full Text]  
• Boni, C., Fisicaro, P., Valdatta, C., Amadei, B., Di Vincenzo, P., Giuberti, T., Laccabue, D., Zerbini, A., Cavalli, A., Missale, G., Bertoletti, A., Ferrari, C. (2007). Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection. J. Virol. 81: 4215-4225 [Abstract] [Full Text]  
• Robek, M. D., Garcia, M. L., Boyd, B. S., Chisari, F. V. (2007). Role of Immunoproteasome Catalytic Subunits in the Immune Response to Hepatitis B Virus. J. Virol. 81: 483-491 [Abstract] [Full Text]  
• Gares, S. L., Fischer, K. P., Congly, S. E., Lacoste, S., Addison, W. R., Tyrrell, D. L., Gutfreund, K. S. (2006). Immunotargeting with CD154 (CD40 Ligand) Enhances DNA Vaccine Responses in Ducks.. CVI 13: 958-965 [Abstract] [Full Text]  
• Bertoletti, A., Gehring, A. J. (2006). The immune response during hepatitis B virus infection. J. Gen. Virol. 87: 1439-1449 [Abstract] [Full Text]  
• Albareda, M. C., Laucella, S. A., Alvarez, M. G., Armenti, A. H., Bertochi, G., Tarleton, R. L., Postan, M. (2006). Trypanosoma cruzi modulates the profile of memory CD8+ T cells in chronic Chagas' disease patients. Int Immunol 18: 465-471 [Abstract] [Full Text]  
• Murray, J. M., Wieland, S. F., Purcell, R. H., Chisari, F. V. (2005). Dynamics of hepatitis B virus clearance in chimpanzees. Proc. Natl. Acad. Sci. USA 102: 17780-17785 [Abstract] [Full Text]  
• Le Mire, M. F., Miller, D. S., Foster, W. K., Burrell, C. J., Jilbert, A. R. (2005). Covalently Closed Circular DNA Is the Predominant Form of Duck Hepatitis B Virus DNA That Persists following Transient Infection. J. Virol. 79: 12242-12252 [Abstract] [Full Text]  
• Wieland, S. F., Chisari, F. V. (2005). Stealth and Cunning: Hepatitis B and Hepatitis C Viruses. J. Virol. 79: 9369-9380 [Full Text]  
• Wieland, S. F., Eustaquio, A., Whitten-Bauer, C., Boyd, B., Chisari, F. V. (2005). Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc. Natl. Acad. Sci. USA 102: 9913-9917 [Abstract] [Full Text]  
• Hutchings, C. L., Gilbert, S. C., Hill, A. V. S., Moore, A. C. (2005). Novel Protein and Poxvirus-Based Vaccine Combinations for Simultaneous Induction of Humoral and Cell-Mediated Immunity. J. Immunol. 175: 599-606 [Abstract] [Full Text]  
• Schirmbeck, R., Riedl, P., Fissolo, N., Lemonnier, F. A., Bertoletti, A., Reimann, J. (2005). Translation from Cryptic Reading Frames of DNA Vaccines Generates an Extended Repertoire of Immunogenic, MHC Class I-Restricted Epitopes. J. Immunol. 174: 4647-4656 [Abstract] [Full Text]  
• Dusheiko, G, Bertoletti, A (2005). Resistance to lamivudine therapy: is there more than meets the eye?. Gut 54: 9-10 [Full Text]  
• Lin, C-L, Tsai, S-L, Lee, T-H, Chien, R-N, Liao, S-K, Liaw, Y-F (2005). High frequency of functional anti-YMDD and -mutant cytotoxic T lymphocytes after in vitro expansion correlates with successful response to lamivudine therapy for chronic hepatitis B. Gut 54: 152-161 [Abstract] [Full Text]  
• Cao, F., Tavis, J. E. (2004). Detection and characterization of cytoplasmic hepatitis B virus reverse transcriptase. J. Gen. Virol. 85: 3353-3360 [Abstract] [Full Text]  
• Mizukoshi, E., Sidney, J., Livingston, B., Ghany, M., Hoofnagle, J. H., Sette, A., Rehermann, B. (2004). Cellular Immune Responses to the Hepatitis B Virus Polymerase. J. Immunol. 173: 5863-5871 [Abstract] [Full Text]  
• Thio, C. L., Mosbruger, T. L., Kaslow, R. A., Karp, C. L., Strathdee, S. A., Vlahov, D., O'Brien, S. J., Astemborski, J., Thomas, D. L. (2004). Cytotoxic T-Lymphocyte Antigen 4 Gene and Recovery from Hepatitis B Virus Infection. J. Virol. 78: 11258-11262 [Abstract] [Full Text]  
• Webster, G. J. M., Reignat, S., Brown, D., Ogg, G. S., Jones, L., Seneviratne, S. L., Williams, R., Dusheiko, G., Bertoletti, A. (2004). Longitudinal Analysis of CD8+ T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy. J. Virol. 78: 5707-5719 [Abstract] [Full Text]  
• Wieland, S., Thimme, R., Purcell, R. H., Chisari, F. V. (2004). Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 101: 6669-6674 [Abstract] [Full Text]  
• Wieland, S. F., Spangenberg, H. C., Thimme, R., Purcell, R. H., Chisari, F. V. (2004). Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. Proc. Natl. Acad. Sci. USA 101: 2129-2134 [Abstract] [Full Text]  
• Thio, C. L., Thomas, D. L., Karacki, P., Gao, X., Marti, D., Kaslow, R. A., Goedert, J. J., Hilgartner, M., Strathdee, S. A., Duggal, P., O'Brien, S. J., Astemborski, J., Carrington, M. (2003). Comprehensive Analysis of Class I and Class II HLA Antigens and Chronic Hepatitis B Virus Infection. J. Virol. 77: 12083-12087 [Abstract] [Full Text]  
• Imamura, T, Yokosuka, O, Kurihara, T, Kanda, T, Fukai, K, Imazeki, F, Saisho, H (2003). Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba, Japan. Gut 52: 1630-1637 [Abstract] [Full Text]  
• Summers, J., Jilbert, A. R., Yang, W., Aldrich, C. E., Saputelli, J., Litwin, S., Toll, E., Mason, W. S. (2003). Inaugural Article: Hepatocyte turnover during resolution of a transient hepadnaviral infection. Proc. Natl. Acad. Sci. USA 100: 11652-11659 [Abstract] [Full Text]  
• Yao, E., Tavis, J. E. (2003). Kinetics of Synthesis and Turnover of the Duck Hepatitis B Virus Reverse Transcriptase. J. Biol. Chem. 278: 1201-1205 [Abstract] [Full Text]  
• Thimme, R., Wieland, S., Steiger, C., Ghrayeb, J., Reimann, K. A., Purcell, R. H., Chisari, F. V. (2002). CD8+ T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection. J. Virol. 77: 68-76 [Abstract] [Full Text]  
• Urbani, S., Boni, C., Missale, G., Elia, G., Cavallo, C., Massari, M., Raimondo, G., Ferrari, C. (2002). Virus-Specific CD8+ Lymphocytes Share the Same Effector-Memory Phenotype but Exhibit Functional Differences in Acute Hepatitis B and C. J. Virol. 76: 12423-12434 [Abstract] [Full Text]  
• Kakimi, K., Isogawa, M., Chung, J., Sette, A., Chisari, F. V. (2002). Immunogenicity and Tolerogenicity of Hepatitis B Virus Structural and Nonstructural Proteins: Implications for Immunotherapy of Persistent Viral Infections. J. Virol. 76: 8609-8620 [Abstract] [Full Text]  
• Alexander, J., Oseroff, C., Dahlberg, C., Qin, M., Ishioka, G., Beebe, M., Fikes, J., Newman, M., Chesnut, R. W., Morton, P. A., Fok, K., Appella, E., Sette, A. (2002). A Decaepitope Polypeptide Primes for Multiple CD8+ IFN-{gamma} and Th Lymphocyte Responses: Evaluation of Multiepitope Polypeptides as a Mode for Vaccine Delivery. J. Immunol. 168: 6189-6198 [Abstract] [Full Text]  
• Mizukoshi, E., Nascimbeni, M., Blaustein, J. B., Mihalik, K., Rice, C. M., Liang, T. J., Feinstone, S. M., Rehermann, B. (2002). Molecular and Immunological Significance of Chimpanzee Major Histocompatibility Complex Haplotypes for Hepatitis C Virus Immune Response and Vaccination Studies. J. Virol. 76: 6093-6103 [Abstract] [Full Text]  
• Garcia-Navarro, R., Blanco-Urgoiti, B., Berraondo, P., Sanchez de la Rosa, R., Vales, A., Hervas-Stubbs, S., Lasarte, J. J., Borras, F., Ruiz, J., Prieto, J. (2001). Protection against Woodchuck Hepatitis Virus (WHV) Infection by Gene Gun Coimmunization with WHV Core and Interleukin-12. J. Virol. 75: 9068-9076 [Abstract] [Full Text]  
• Jager, D, Jager, E, Knuth, A (2001). Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J. Clin. Pathol. 54: 669-674 [Abstract] [Full Text]  
• Thimme, R., Chang, K.-M., Pemberton, J., Sette, A., Chisari, F. V. (2001). Degenerate Immunogenicity of an HLA-A2-Restricted Hepatitis B Virus Nucleocapsid Cytotoxic T-Lymphocyte Epitope That Is Also Presented by HLA-B51. J. Virol. 75: 3984-3987 [Abstract] [Full Text]  
• Allen, T. M., Mothé, B. R., Sidney, J., Jing, P., Dzuris, J. L., Liebl, M. E., Vogel, T. U., O'Connor, D. H., Wang, X., Wussow, M. C., Thomson, J. A., Altman, J. D., Watkins, D. I., Sette, A. (2001). CD8+ Lymphocytes from Simian Immunodeficiency Virus-Infected Rhesus Macaques Recognize 14 Different Epitopes Bound by the Major Histocompatibility Complex Class I Molecule Mamu-A*01: Implications for Vaccine Design and Testing. J. Virol. 75: 738-749 [Abstract] [Full Text]  
• Sette, A. D., Oseroff, C., Sidney, J., Alexander, J., Chesnut, R. W., Kakimi, K., Guidotti, L. G., Chisari, F. V. (2001). Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice. J. Immunol. 166: 1389-1397 [Abstract] [Full Text]  
• Khakoo, S I, Ling, R, Scott, I, Dodi, A I, Harrison, T J, Dusheiko, G M, Madrigal, J A (2000). Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals. Gut 47: 137-143 [Abstract] [Full Text]  
• Crotzer, V. L., Christian, R. E., Brooks, J. M., Shabanowitz, J., Settlage, R. E., Marto, J. A., White, F. M., Rickinson, A. B., Hunt, D. F., Engelhard, V. H. (2000). Immunodominance Among EBV-Derived Epitopes Restricted by HLA-B27 Does Not Correlate with Epitope Abundance in EBV-Transformed B-Lymphoblastoid Cell Lines. J. Immunol. 164: 6120-6129 [Abstract] [Full Text]  
• Michalak, T. I., Hodgson, P. D., Churchill, N. D. (2000). Posttranscriptional Inhibition of Class I Major Histocompatibility Complex Presentation on Hepatocytes and Lymphoid Cells in Chronic Woodchuck Hepatitis Virus Infection. J. Virol. 74: 4483-4494 [Abstract] [Full Text]  
• Rehermann, B. (2000). Intrahepatic T Cells in Hepatitis B: Viral Control versus Liver Cell Injury. J. Exp. Med. 191: 1263-1268 [Abstract] [Full Text]  
• Maini, M. K., Boni, C., Lee, C. K., Larrubia, J. R., Reignat, S., Ogg, G. S., King, A. S., Herberg, J., Gilson, R., Alisa, A., Williams, R., Vergani, D., Naoumov, N. V., Ferrari, C., Bertoletti, A. (2000). The Role of Virus-specific CD8+ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection. J. Exp. Med. 191: 1269-1280 [Abstract] [Full Text]  
• Chisari, F. V. (2000). Viruses, Immunity, and Cancer: Lessons from Hepatitis B. Am. J. Pathol. 156: 1117-1132 [Full Text]  
• Sijts, A. J.A.M., Ruppert, T., Rehermann, B., Schmidt, M., Koszinowski, U., Kloetzel, P.-M. (2000). Efficient Generation of a Hepatitis B Virus Cytotoxic T Lymphocyte Epitope Requires the Structural Features of Immunoproteasomes. J. Exp. Med. 191: 503-514 [Abstract] [Full Text]  
• Lauvau, G., Kakimi, K., Niedermann, G., Ostankovitch, M., Yotnda, P., Firat, H., Chisari, F. V., van Endert, P. M. (1999). Human Transporters Associated with Antigen Processing (TAPs) Select Epitope Precursor Peptides for Processing in the Endoplasmic Reticulum and Presentation to T Cells. J. Exp. Med. 190: 1227-1240 [Abstract] [Full Text]  
• He, X.-S., Rehermann, B., Lopez-Labrador, F. X., Boisvert, J., Cheung, R., Mumm, J., Wedemeyer, H., Berenguer, M., Wright, T. L., Davis, M. M., Greenberg, H. B. (1999). Quantitative analysis of hepatitis C virus-specific CD8+ T cells in peripheral blood and liver using peptide-MHC tetramers. Proc. Natl. Acad. Sci. USA 96: 5692-5697 [Abstract] [Full Text]  
• zu Putlitz, J., Lanford, R. E., Carlson, R. I., Notvall, L., de la Monte, S. M., Wands, J. R. (1999). Properties of Monoclonal Antibodies Directed against Hepatitis B Virus Polymerase Protein. J. Virol. 73: 4188-4196 [Abstract] [Full Text]  
• Ishioka, G. Y., Fikes, J., Hermanson, G., Livingston, B., Crimi, C., Qin, M., France del Guercio, M., Oseroff, C., Dahlberg, C., Alexander, J., Chesnut, R. W., Sette, A. (1999). Utilization of MHC Class I Transgenic Mice for Development of Minigene DNA Vaccines Encoding Multiple HLA-Restricted CTL Epitopes. J. Immunol. 162: 3915-3925 [Abstract] [Full Text]  
• Chang, K.-M., Gruener, N. H., Southwood, S., Sidney, J., Pape, G. R., Chisari, F. V., Sette, A. (1999). Identification of HLA-A3 and -B7-Restricted CTL Response to Hepatitis C Virus in Patients with Acute and Chronic Hepatitis C. J. Immunol. 162: 1156-1164 [Abstract] [Full Text]  
• Ishikawa, T., Kono, D., Chung, J., Fowler, P., Theofilopoulos, A., Kakumu, S., Chisari, F. V. (1998). Polyclonality and Multispecificity of the CTL Response to a Single Viral Epitope. J. Immunol. 161: 5842-5850 [Abstract] [Full Text]  
• Shimizu, Y., Guidotti, L. G., Fowler, P., Chisari, F. V. (1998). Dendritic Cell Immunization Breaks Cytotoxic T Lymphocyte Tolerance in Hepatitis B Virus Transgenic Mice. J. Immunol. 161: 4520-4529 [Abstract] [Full Text]  
• Bertoni, R., Sette, A., Sidney, J., Guidotti, L. G., Shapiro, M., Purcell, R., Chisari, F. V. (1998). Human Class I Supertypes and CTL Repertoires Extend to Chimpanzees. J. Immunol. 161: 4447-4455 [Abstract] [Full Text]  
• Lemon, S. M., Thomas, D. L. (1997). Vaccines to Prevent Viral Hepatitis. NEJM 336: 196-204 [Full Text]  
• Liu, C.-C., Young, L. H.Y., Young, J. D.-E (1996). Lymphocyte-Mediated Cytolysis and Disease. NEJM 335: 1651-1659 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS