The Role of Virus-Specific Cd8+ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection

doi:10.1084/jem.191.8.1269

Published online 17 April 2000.

This Article

	Full Text
	Full Text (PDF, 274K)
	PPT slides of all figures
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Maini, M. K.
	Articles by Bertoletti, A.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Maini, M. K.
	Articles by Bertoletti, A.

Social Bookmarking

	What's this?

© The Rockefeller University Press, 0022-1007/2000/4/1269/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 8, April 17, 2000 1269-1280

Original Article

The Role of Virus-Specific Cd8⁺ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection

Mala K. Maini^a^,b, Carolina Boni^c, Chun Kyon Lee^a, Juan R. Larrubia^a, Stephanie Reignat^a, Graham S. Ogg^d, Abigail S. King^d, Jethro Herberg^a, Richard Gilson^b, Akeem Alisa^e, Roger Williams^a, Diego Vergani^a, Nikolai V. Naoumov^a, Carlo Ferrari^c, and Antonio Bertoletti^a

^a Institute of Hepatology, University College London and University College of London Hospitals, London WC1E 6HX, United Kingdom
^b Department of Sexually Transmitted Diseases, University College London and University College of London Hospitals, London WC1E 6HX, United Kingdom
^c Laboratorio Immunopatologia Virale, Ospedale di Parma, 43100 Parma, Italy
^d Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
^e Cromwell Hospital, London SW5 0TU, United Kingdom
Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, UK.44-171-380-040544-171-209-6516

a.bertoletti{at}ucl.ac.uk

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognitionof infected hepatocytes by HBV-specific CD8 cells has been assumedto be the central mechanism causing both liver damage and viruscontrol. To understand the role of cytotoxic T cells in thepathogenesis of HBV infection, we used functional assays thatrequire T cell expansion in vitro and human histocompatibilityleukocyte antigen (HLA)-peptide tetramers that allow directex vivo quantification of circulating and liver-infiltratingHBV-specific CD8 cells. Two groups of patients with persistentHBV infection were studied: one without liver inflammation andHBV replication, the other with liver inflammation and a highlevel of HBV replication. Contrary to expectation, a high frequencyof intrahepatic HBV-specific CD8 cells was found in the absenceof hepatic immunopathology. In contrast, virus-specific T cellswere more diluted among liver infiltrates in viremic patients,but their absolute number was similar because of the massivecellular infiltration. Furthermore, inhibition of HBV replicationwas associated with the presence of a circulating reservoirof CD8⁺ cells able to expand after specific virus recognitionthat was not detectable in highly viremic patients with liverinflammation.

These results show that in the presence of an effective HBV-specificCD8 response, inhibition of virus replication can be independentof liver damage. When the HBV-specific CD8 response is unableto control virus replication, it may contribute to liver pathologynot only directly but by causing the recruitment of nonvirus-specificT cells.

Key Words: hepatitis • tetramers • antiviral cytotoxic T lymphocytes • cell migration • immunopathology

Abbreviations used in this paper: ALT, alanine transaminase;HBc, HBV core; HBe, HBV e; HBs, HBV surface; HBV, hepatitisB virus; HCV, hepatitis C virus; Tc 18–27, core 18–27HLA-A2 tetrameric complex; Te 335–343, envelope 335–343HLA-A2 tetrameric complex; Tp 575–583, polymerase 575–583HLA-A2 tetrameric complex.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Price, P., Murdoch, D. M., Agarwal, U., Lewin, S. R., Elliott, J. H., French, M. A. (2009). Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms. Clin. Microbiol. Rev. 22: 651-663 [Abstract] [Full Text]
Chang, J. J., Sirivichayakul, S., Avihingsanon, A., Thompson, A. J. V., Revill, P., Iser, D., Slavin, J., Buranapraditkun, S., Marks, P., Matthews, G., Cooper, D. A., Kent, S. J., Cameron, P. U., Sasadeusz, J., Desmond, P., Locarnini, S., Dore, G. J., Ruxrungtham, K., Lewin, S. R. (2009). Impaired Quality of the Hepatitis B Virus (HBV)-Specific T-Cell Response in Human Immunodeficiency Virus Type 1-HBV Coinfection. J. Virol. 83: 7649-7658 [Abstract] [Full Text]
Riedl, P., Wieland, A., Lamberth, K., Buus, S., Lemonnier, F., Reifenberg, K., Reimann, J., Schirmbeck, R. (2009). Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential. J. Immunol. 183: 370-380 [Abstract] [Full Text]
Fisicaro, P, Valdatta, C, Boni, C, Massari, M, Mori, C, Zerbini, A, Orlandini, A, Sacchelli, L, Missale, G, Ferrari, C (2009). Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 58: 974-982 [Abstract] [Full Text]
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]
Das, A., Hoare, M., Davies, N., Lopes, A. R., Dunn, C., Kennedy, P. T.F., Alexander, G., Finney, H., Lawson, A., Plunkett, F. J., Bertoletti, A., Akbar, A. N., Maini, M. K. (2008). Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. JEM 205: 2111-2124 [Abstract] [Full Text]
Lukens, J. R., Cruise, M. W., Lassen, M. G., Hahn, Y. S. (2008). Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model. J. Immunol. 180: 4875-4884 [Abstract] [Full Text]
Lu, M., Yao, X., Xu, Y., Lorenz, H., Dahmen, U., Chi, H., Dirsch, O., Kemper, T., He, L., Glebe, D., Gerlich, W. H., Wen, Y., Roggendorf, M. (2008). Combination of an Antiviral Drug and Immunomodulation against Hepadnaviral Infection in the Woodchuck Model. J. Virol. 82: 2598-2603 [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]
Singh, A., Wuthrich, M., Klein, B., Suresh, M. (2007). Indirect Regulation of CD4 T-Cell Responses by Tumor Necrosis Factor Receptors in an Acute Viral Infection. J. Virol. 81: 6502-6512 [Abstract] [Full Text]
Chen, L., Zhang, Z., Chen, W., Zhang, Z., Li, Y., Shi, M., Zhang, J., Chen, L., Wang, S., Wang, F.-S. (2007). B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B. J. Immunol. 178: 6634-6641 [Abstract] [Full Text]
Dunn, C., Brunetto, M., Reynolds, G., Christophides, T., Kennedy, P. T., Lampertico, P., Das, A., Lopes, A. R., Borrow, P., Williams, K., Humphreys, E., Afford, S., Adams, D. H., Bertoletti, A., Maini, M. K. (2007). Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. JEM 204: 667-680 [Abstract] [Full Text]
Gehring, A. J., Sun, D., Kennedy, P. T. F., Nolte-'t Hoen, E., Lim, S. G., Wasser, S., Selden, C., Maini, M. K., Davis, D. M., Nassal, M., Bertoletti, A. (2007). The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function. J. Virol. 81: 2940-2949 [Abstract] [Full Text]
Keating, R., Yue, W., Rutigliano, J. A., So, J., Olivas, E., Thomas, P. G., Doherty, P. C. (2007). Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill. J. Immunol. 178: 2737-2745 [Abstract] [Full Text]
Bergthaler, A., Merkler, D., Horvath, E., Bestmann, L., Pinschewer, D. D. (2007). Contributions of the lymphocytic choriomeningitis virus glycoprotein and polymerase to strain-specific differences in murine liver pathogenicity. J. Gen. Virol. 88: 592-603 [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]
Chen, A., Wang, L., Zhang, J., Zou, L., Jia, Z., Zhou, W., Wan, Y., Wu, Y. (2005). H-2 Kd-Restricted Hepatitis B Virus-Derived Epitope Whose Specific CD8+ T Lymphocytes Can Produce Gamma Interferon without Cytotoxicity. J. Virol. 79: 5568-5576 [Abstract] [Full Text]
Franzese, O., Kennedy, P. T. F., Gehring, A. J., Gotto, J., Williams, R., Maini, M. K., Bertoletti, A. (2005). Modulation of the CD8+-T-Cell Response by CD4+ CD25+ Regulatory T Cells in Patients with Hepatitis B Virus Infection. J. Virol. 79: 3322-3328 [Abstract] [Full Text]
Chang, J. J., Wightman, F., Bartholomeusz, A., Ayres, A., Kent, S. J., Sasadeusz, J., Lewin, S. R. (2005). Reduced Hepatitis B Virus (HBV)-Specific CD4+ T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy. J. Virol. 79: 3038-3051 [Abstract] [Full Text]
Carotenuto, P., van Riel, D., Artsen, A., Bruijns, S., Uytdehaag, F. G., Laman, J. D., van Nunen, A. B., Zondervan, P. E., De Man, R. A., Osterhaus, A. D., Pontesilli, O. (2005). Antiviral Treatment with Alpha Interferon Up-Regulates CD14 on Liver Macrophages and Its Soluble Form in Patients with Chronic Hepatitis B. Antimicrob. Agents Chemother. 49: 590-599 [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]
Huang, Y.-H., Tao, M.-H., Hu, C.-p., Syu, W.-J., Wu, J.-C. (2004). Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus. J. Gen. Virol. 85: 3089-3098 [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]
Suresh, M., Gao, X., Fischer, C., Miller, N. E., Tewari, K. (2004). Dissection of Antiviral and Immune Regulatory Functions of Tumor Necrosis Factor Receptors in a Chronic Lymphocytic Choriomeningitis Virus Infection. J. Virol. 78: 3906-3918 [Abstract] [Full Text]
Zhou, S., Ou, R., Huang, L., Price, G. E., Moskophidis, D. (2004). Differential Tissue-Specific Regulation of Antiviral CD8+ T-Cell Immune Responses during Chronic Viral Infection. J. Virol. 78: 3578-3600 [Abstract] [Full Text]
Bocharov, G., Ludewig, B., Bertoletti, A., Klenerman, P., Junt, T., Krebs, P., Luzyanina, T., Fraser, C., Anderson, R. M. (2004). Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses. J. Virol. 78: 2247-2254 [Abstract] [Full Text]
Tewari, K., Sacha, J., Gao, X., Suresh, M. (2004). Effect of Chronic Viral Infection on Epitope Selection, Cytokine Production, and Surface Phenotype of CD8 T Cells and the Role of IFN-{gamma} Receptor in Immune Regulation. J. Immunol. 172: 1491-1500 [Abstract] [Full Text]
Lin, S.-J., Shu, P.-Y., Chang, C., Ng, A.-K., Hu, C.-p. (2003). IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B. J. Immunol. 171: 4708-4716 [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]
Sitia, G., Isogawa, M., Kakimi, K., Wieland, S. F., Chisari, F. V., Guidotti, L. G. (2002). Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes. Proc. Natl. Acad. Sci. USA 99: 13717-13722 [Abstract] [Full Text]
Kang, B.-S., Lyman, M. A., Kim, B. S. (2002). The Majority of Infiltrating CD8+ T Cells in the Central Nervous System of Susceptible SJL/J Mice Infected with Theiler's Virus Are Virus Specific and Fully Functional. J. Virol. 76: 6577-6585 [Abstract] [Full Text]
Kakimi, K., Lane, T. E., Wieland, S., Asensio, V. C., Campbell, I. L., Chisari, F. V., Guidotti, L. G. (2001). Blocking Chemokine Responsive to {gamma}-2/Interferon (IFN)-{gamma} Inducible Protein and Monokine Induced by IFN-{gamma} Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus-specific Cytotoxic T Lymphocytes. JEM 194: 1755-1766 [Abstract] [Full Text]
Pathan, A. A., Wilkinson, K. A., Klenerman, P., McShane, H., Davidson, R. N., Pasvol, G., Hill, A. V. S., Lalvani, A. (2001). Direct Ex Vivo Analysis of Antigen-Specific IFN-{gamma}-Secreting CD4 T Cells in Mycobacterium tuberculosis-Infected Individuals: Associations with Clinical Disease State and Effect of Treatment. J. Immunol. 167: 5217-5225 [Abstract] [Full Text]
Liu, Z.-X., Govindarajan, S., Okamoto, S., Dennert, G. (2001). Fas-Mediated Apoptosis Causes Elimination of Virus-Specific Cytotoxic T Cells in the Virus-Infected Liver. J. Immunol. 166: 3035-3041 [Abstract] [Full Text]
Rehermann, B. (2000). Intrahepatic T Cells in Hepatitis B: Viral Control versus Liver Cell Injury. JEM 191: 1263-1268 [Full Text]
Reignat, S., Webster, G. J.M., Brown, D., Ogg, G. S., King, A., Seneviratne, S. L., Dusheiko, G., Williams, R., Maini, M. K., Bertoletti, A. (2002). Escaping High Viral Load Exhaustion: CD8 Cells with Altered Tetramer Binding in Chronic Hepatitis B Virus Infection. JEM 195: 1089-1101 [Abstract] [Full Text]