Hepatitis B virus (HBV) infection is a preferential "Asian affair"; of the 350 million people suffering from chronic HBV infection worldwide, approximately 75% are in Asia.

Research in my laboratory focuses on understanding the role of T cells in HBV pathogenesis and on developing immune therapeutic strategies for treating chronic HBV infection. Different methodological approaches (high dimensional flow cytometry, gene expression profile, laser microdissection) are utilized to analyze the HBV-specific T cell repertoire and the function of HBV-specific CD8 T cells in different clinical conditions. We are particularly interested to redefine the function of T cells in the liver environment and understand the molecular mechanisms responsible for T cell exhaustion. In addition, the laboratory is actively developing strategies to restore HBV-specific immunity in chronic HBV patients or to increase the bioavailability of cytokines/drugs into infected hepatocytes. Selection of virus-specific CD8 T cells from patients allows isolation of their T cell receptors that are then used to engineer TCR-redirected T cells. Monoclonal antibodies targeting HBV peptide/MHC complexes on HBV infected hepatocytes (TCR-like antibodies) are also produced. They represent an invaluable tool to elucidate the immunological and virological features of HBV infected cells and are explored as a novel therapeutic platform for personalized health care of HBV infected patients.

Immune-pathogenesis of chronic viral hepatitis.

1. Impact of host and virus heterogeneity on HBV specific T cell repertoire.
2. Reprogramming "exhausted" T cells through modulation of the epigenetic chromatin signature.
3. The influence of liver environment on T cell function.

Therapeutic Platform

1. TCR-redirected T cells, TCR-like antibodies and soluble TCRs

Increased Levels of Arginase in Patients With Acute Hepatitis B Suppress Antiviral T Cells.Elena Sandalova, Diletta Laccabue, Carolina Boni, Tsunamasa Watanabe, Anthony Tan, Ho Zi Zong, Carlo Ferrari and Antonio Bertoletti. Gastroenterology 2012, pp. 1-21

Targeted Delivery of Inteferon- α To HBV-Infected Cells Using T Cell Receptor-Like Antibodies. Changhua Ji, Konduru SR Sastry, Georg Tiefenthaler, Jennifer Cano, Tenny Tang, ZI Zong Ho, Denise Teoh, Sandhya Bohini, Antony Chen, Surya Sankuratri, Paul A Macary, Patrick Kennedy, Han Ma, Stefan Ries, Klaus Klumpp, Erhard Kopetzki, Antonio Bertoletti. Hepatology 2012. (Article in press)

Licensing Virus-Specific T Cells to Secrete the Neutrophil Attracting Chemokine CXCL-8 during Hepatitis B Virus Infection. Adam J. Gehring, Sarene Koh, Adeline Chia, Komathi Paramasivam, Valerie Suk Peng Chew, Zi Zong Ho, Kang Hoe Lee, Mala K. Maini, Krishnakumar Madhavan, Seng Gee Lim, Antonio Bertoletti. Plos one 2011 6(8): e23330. doi:10.1371/journal.pone.0023330

Engineering Virus-specific T cell immunity to Target Chronic Hepatitis B Virus Infection and HBV-related Hepatocellular Carcinoma. A.J. Gehring, S Xue, Z.Z. Ho, D. Teoh, C. Ruedl A. Chia, S. Koh, SG Lim, MK. Maini, H. Stauss and A Bertoletti. J. Hepatol, 2011, p. 103-110, Vol 55, Issue 1.

Stability screening of arrays of major histocompatibility complexes on combinatorially encoded flow cytometry beads. Chew SL, Or MY, Chang CX, Gehring AJ, Bertoletti A, Grotenbreg GM. J. Biol Chem 2011 June 16, DOI 10.1074/jbc.m111.262691

Sources of diversity in T cell epitope discovery. Chang CX, Dai L, Tan ZW, Choo JA, Bertoletti A, Grotenbreg GM. Front Biosci. 2011 Jun 1; 17:3014-35.

Engineering T cells specific for a dominant SARS coronavirus CD8 T cell epitope" by Hsueh Ling Janice Oh, Adeline Chia, Cynthia Xin Lei Chang, Hoe Nam Leong, Khoon Lin Ling, Gijsbert Grotenbreg, Adam Gehring, Yee Joo Tan, and Antonio Bertoletti. J. Virol 2011 (Article in press) (JVI05039-11R2)

Targeting Hepatitis B virus infected cells with a T-cell receptor like antibody. Konduru S. R. Sastry,¹ Chien Tei Too, Kaval Kaur, Adam J. Gehring, Lionel Low, Alia Javiad, Teresa Pollicino, Li Li, Patrick T. F. Kennedy, Uri Lopatin, Paul A. Macary, and Antonio Bertoletti . Journal of Virology, 2011 March, p. 1935-1942, Vol. 85, No. 5

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg+/HBeAg- mothers. Koumbi L, Bertoletti A, Anastasiadou V, Machaira M, Goh W, Papadopoulos NG, Kafetzis DA, Papaevangelou V. Cell Mol Immunol. 2010 Nov;7(6):454-8.

Characterization of CD8+ T-cell response in acute and resolved Hepatitis A virus infection. Schulte I, Hitziger T, Giugliano S, Timm J, Gold H, Heinemann FM, Khudyakov Y, Strasser M, König C, Castermans E, Mok JY, van Esch WJ, Bertoletti A, Schumacher TN, Roggendorf M. J Hepatol,  2010 Sep 15.

Contribution of herpesvirus specific CD8 T cells to anti-viral T cell response in humans. Sandalova E, Laccabue D, Boni C, Tan AT, Fink K, Ooi EE, Chua R, Shafaeddin Schreve B, Ferrari C, Bertoletti A. PLoS Pathog. 2010 Aug 19;6(8).

Watanabe T, Bertoletti A, Tanoto TA. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat. 2010 Jul;17(7):453-8.

A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. Tan AT, Koh S, Goh W, Zhe HY, Gehring AJ, Lim SG, Bertoletti A. J Hepatol. 2010 Mar;52(3):330-9.

Bertoletti A, Maini MK, Ferrari C. The host-pathogen interaction during HBV infection: immunological controversies. Antivir Ther. 2010;15 Suppl 3:15-24.

Bertoletti A, Gehring A. Therapeutic vaccination and novel strategies to treat chronic HBV infection. Expert Review Hepatology and Gastroenterology 2009 Oct : 3 (5): 561-9.

Bertoletti, A.; Tan, A.; Gehring, A. HBV-Specific Adaptive Immunity. Viruses 2009, 1(2), 91-103; doi:10.3390/v1020091.

Profile of tumor antigen-specific CD8+ T cells in patients with hepatitis B virus-related hepatocellular carcinoma. A J Gehring, ZZ Ho S Koh, A Chia, KH Lee, KC Tan, SG Lee, A Bertoletti. Gastroenterology 2009,137: 682-690.

A Das, M Hoare^, N Davies, AR Lopes, C. Dunn, PTF Kennedy, G. Alexander, H Finney, A Lawson, FJ Plunkett, A Bertoletti , AN. Akbar, MK. Maini. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection J Exp Med. 2008 Sep 1;205(9):2111-24.

AR.Lopes, P Kellam, A.Das, C. Dunn, A.J.Gehring, A. Kwan, J. Turner, RJ Gilson, A. Bertoletti, MK. Maini. Bim-Mediated deletion of antigen-specific CD8T cells in patients unable to control Hepatis B virus control. J. Clin. Invest. 2008,118(5):1835-45

Tanoto Tan A, Koh S, Goh V, Bertoletti A. Understanding the immunopathogenesis of chronic hepatitis B: an Asian prospective. 2008, J. Gastroenterology and Hepatology, 3: 833-43.

A. Tan, E. Loggi, C. Boni, A. Chia, A.J. Gehring, KS Sastry, V. Goh, P. Fisicaro, P. Andreone, C. Brader, SG Lim,  C. Ferrari, F. Bihl, A. Bertoletti. Host ethnicity and virus genotype shape the HBV-specific T cell repertoire. , J. Virol. 2008, 82: 10986-97.

Increased Levels of Arginase in Patients With Acute Hepatitis B Suppress Antiviral T Cells.Elena Sandalova, Diletta Laccabue, Carolina Boni, Tsunamasa Watanabe, Anthony Tan, Ho Zi Zong, Carlo Ferrari and Antonio Bertoletti. Gastroenterology 2012, pp. 1-21

Targeted Delivery of Inteferon- α To HBV-Infected Cells Using T Cell Receptor-Like Antibodies. Changhua Ji, Konduru SR Sastry, Georg Tiefenthaler, Jennifer Cano, Tenny Tang, ZI Zong Ho, Denise Teoh, Sandhya Bohini, Antony Chen, Surya Sankuratri, Paul A Macary, Patrick Kennedy, Han Ma, Stefan Ries, Klaus Klumpp, Erhard Kopetzki, Antonio Bertoletti. Hepatology 2012. (Article in press)

Adeline Chia
Lab Manager

Juandy Jo
Research Fellow

Michelle Hong
Research Fellow

Tan Anthony Tanoto
Research Fellow

Zack Ho
Senior Research Officer

Nasirah Banu
Research Officer 

Komathi Paramasivam
Research Officer 

Sarene Koh
PhD Student

Anneta Naidoo
PhD Student