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Antonio Bertoletti

Professor

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I trained a specialist in Infectious Diseases and have always been interested in the immunological control of persistent viral infections, particularly Hepatitis B (HBV).

During my research career, first in USA (The Scripps Research Institute) and then in Italy (University of Parma), I was the first to characterize hepatitis B virus (HBV) specific human CD8 T cells in HBV infected patients (Proc. Natl. Acad. Sci. USA 1991 88: 10445), and to define the effect of HBV mutations in HBV-specific CTL function (Nature 1994 369: 407-J. Exp. Med. 1994 180: 933).

I moved to London (University College of London) in 1997, where I pioneered the use of HLA-tetramers in HBV infected subjects and used them to characterize the role of HBV-specific T cells in viral control and disease pathogenesis (J. Exp. Med. 2000, 191: 1269 ,J. Exp. Med, 2002 195: 1089; J. Virol, 2004, 78;5707)

In 2006 I moved to Singapore, motivated by the opportunity to build on our understanding of HBV infection, a worldwide serious health problem that is over-represented in Asia and I became Director of Infection and Immunity Program at the Singapore Institute for Clinical Sciences (A*STAR) until 2013, after which I joined as a Professor in the Emerging Infectious Disease Programme at Duke-NUS Medical School in the same year.

In my laboratory we characterized the impact of Asian HLA- class I profile and HBV genotypes on on HBV immunopathogenesis (J. Virol. 2008 82: 10986, Gastroenterology 2012, 43 :637; J Clin Invest. 2013 123(9):3766).

Our current research focuses on the development of new immunological based therapies (TCR-redirected T cells, HLA-peptide specific antibodies) for the treatment of HBV and Hepatocellular carcinoma (HCC), and the characterization of human intra-sinusoidal hepatic immune system.

Our laboratory focuses on understanding how HBV infection evades or triggers the host-immunity that causes viral control and/or liver inflammation.

These immune mechanisms are preferentially studied in patient’s samples directly (peripheral blood and liver biopsies), obtained with active collaborations with different clinical groups. We also utilize human-chimeric SCID mouse reconstituted with human hepatocytes and immune cells that mimics HBV infection.

Our major projects are focused on:

  • Adoptive T-cell Therapy
    • This focuses on TCR-redirected T cells that can recognize and target Hepatitis B virus in order to reconstitute HBV-specific Immunity in patients with chronic Hepatitis B or Hepatocellular Carcinoma (HCC). We are also working on ways to improve the efficacy of these engineered cells and the selection of the correct TCR for personalized treatment of HBV-related HCC patients. Understanding the liver microenvironment and how it affects the behavior of T-cell receptor engineered T cells is crucial in order for adoptive cell therapy approaches to be successful in the treatment of chronic HBV infection or related hepatocellular carcinoma. We have developed an imaging-based 3-dimensional microdevice assay in collaboration as a pre-clinical test bench to evaluate the functionality of engineered T cells in environments similar to that encountered during actual adoptive therapy.
  • 3-Dimensional Microfluidics Platform 
    • Adaptive immune response in HBV infection and how it might evolve and mature over time; this includes the humoral compartment in which the role of B-cells in HBV infection is relatively poorly understood, and cell-mediated immunity in which T-cells are important for anti-viral control. Understanding the mechanism of HBV vertical infection (mother to child) and the impact that HBV infection exert on the maturation of the host immune system.
  • Adaptive immune response in HBV infection and how it might evolve and mature over time; this includes the humoral compartment in which the role of B-cells in HBV infection is relatively poorly understood, and cell-mediated immunity in which T-cells are important for anti-viral control.
  • Understanding the mechanism of HBV vertical infection (mother to child) and the impact that HBV infection exert on the maturation of the host immune system

Cheng Y, Zhu YO, Becht E, Aw P, Chen J, Poidinger M, de Sessions PF, Hibberd ML, Bertoletti A, Lim SG, Newell EW. Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection. Sci Immunol. 2019 Feb 8;4(32). pii: eaau6905. doi: 10.1126/sciimmunol.aau6905.

Tan AT, Yang N, Krishnamoorthy TL, Oei V, Chua A, Xinyuan Z, Si TH, Chia A, Le Bert N, Low D, Tan HK, Kumar R, Irani FG, Zong HZ, Zhang Q, Guccione E, Lu-En W, Koh S, Hwang W, Chow WC, Bertoletti A, Use of Expression Profiles of HBV DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy, Gastroenterology (2019), doi: https://doi.org/10.1053/j.gastro.2019.01.251.

Bertoletti A, Kennedy PTF. HBV antiviral immunity: not all CD8 T cells are born equal, Gut. 2019 Jan 30. pii: gutjnl-2018-317959. doi: 10.1136/gutjnl-2018-317959.

Khakpoor A, Ni Y, Chen A, Ho ZZ, Oei V, Yang N, Giri R, Chow JX, Tan AT, Kennedy PT, Maini M, Urban S, Bertoletti A. Spatiotemporal Differences in Presentation of CD8 T Cell Epitopes during Hepatitis B Virus Infection. J Virol. 2019 Feb 5;93(4). pii: e01457-18. doi: 10.1128/JVI.01457-18

Otano I, Escors D, Schurich A, Singh H, Robertson F, Davidson BR, Fusai G, Vargas FA, Tan ZMD, Aw JYJ, Hansi N, Kennedy PTF, Xue SA, Stauss HJ, Bertoletti A, Pavesi A, Maini MK. Molecular Recalibration of PD-1+ Antigen-Specific T Cells from Blood and Liver. Mol Ther. 2018 Nov 7;26(11):2553-2566. doi: 10.1016/j.ymthe.2018.08.013.

Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW, Frey C, Hung M, Novikov N, Fletcher S, Kennedy PT, Bertoletti A. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest. 2018 Aug 7. pii: 121957. doi: 10.1172/JCI121957.

Zhao X, Sankaran S, Yap J, Too CT, Ho ZZ, Dolton G, Legut M, Ren EC, Sewell AK, Bertoletti A, MacAry PA, Brzostek J, Gascoigne NRJ. Nonstimulatory peptide-MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling. Nat Commun. 2018 Jul 13;9(1):2716. doi: 10.1038/s41467-018-05288-0.

Urban S, Bertoletti A. Editorial overview: Antiviral strategies: Virological and immunological basis for HBV cure. Curr Opin Virol. 2018 Jun;30:iv-vi. doi: 10.1016/j.coviro.2018.05.001.

Lee SWL, Adriani G, Ceccarello E, Pavesi A, Tan AT, Bertoletti A, Kamm RD, Wong SC. Characterizing the Role of Monocytes in T Cell Cancer Immunotherapy Using a 3D Microfluidic Model. Front Immunol. 2018 Mar 6;9:416. doi: 10.3389/fimmu.2018.00416. eCollection 2018.

Koh S, Kah J, Tham CYL, Yang N, Ceccarello E, Chia A, Chen M, Khakpoor A, Pavesi A, Tan AT, Dandri M, Bertoletti A. Nonlytic Lymphocytes Engineered to Express Virus-Specific T-Cell Receptors Limit HBV Infection by Activating APOBEC3. Gastroenterology. 2018 Jul; 155(1):180-193.e6. doi: 10.1053/j.gastro.2018.03.027. Epub 2018 Mar 14.

Dharmadhikari B, Nickles E, Harfuddin Z, Ishak NDB, Zeng Q, Bertoletti A, Schwarz H. CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype. Cancer Immunol Immunother. 2018 Jun;67(6):893-905. doi: 10.1007/s00262-018-2144-x.

Bertoletti A, Bert NL. Immunotherapy for Chronic Hepatitis B Virus Infection. Gut Liver. 2018 Jan 11. doi: 10.5009/gnl17233.

Rivino L, Le Bert N, Gill US, Kunasegaran K, Cheng Y, Tan DZ, Becht E, Hansi NK, Foster GR, Su TH, Tseng TC, Lim SG, Kao JH, Newell EW, Kennedy PT, Bertoletti A. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest. 2018 Feb 1;128(2):668-681. doi: 10.1172/JCI92812. Epub 2018 Jan 8.

Bertoletti A, Kennedy PTF, Durantel D. HBV infection and HCC: the 'dangerous liaisons'. Gut. 2018 May;67(5):787-788. doi: 10.1136/gutjnl-2017-315528.

Bertoletti A, Tan AT, Koh S. T-cell therapy for chronic viral hepatitis. Cytotherapy. 2017 Nov;19(11):1317-1324. doi: 10.1016/j.jcyt.2017.07.011. Epub 2017 Aug 25.

Bist P, Cheong WS, Ng A, Dikshit N, Kim BH, Pulloor NK, Khameneh HJ, Hedl M, Shenoy AR, Balamuralidhar V, Malik NBA, Hong M, Neutzner A, Chin KC, Kobayashi KS, Bertoletti A, Mortellaro A, Abraham C, MacMicking JD, Xavier RJ, Sukumaran B. Erratum: E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. Nat Commun. 2017 Aug 18;8:16141. doi: 10.1038/ncomms16141.

Pavesi A, Tan AT, Koh S, Chia A, Colombo M, Antonecchia E, Miccolis C, Ceccarello E, Adriani G, Raimondi MT, Kamm RD, Bertoletti A. A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors. JCI Insight. 2017 Jun 15;2(12). pii: 89762. doi: 10.1172/jci.insight.89762.

Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O, Hong ML, Naik S, Quaglia A, Bertoletti A, Kennedy PT. HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant. Gastroenterology. 2016 Nov;151(5):986-998.e4. doi: 10.1053/j.gastro.2016.07.012.

Hong M, Sandalova E, Low D, Gehring AJ, Fieni S, Amadei B, Urbani S, Chong YS, Guccione E, Bertoletti A. Trained immunity in newborn infants of HBV-infected mothers. Nat Commun. 2015 Mar 25;6:6588. doi: 10.1038/ncomms7588.