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Antonio Bertoletti

Professor

Email

Contact: 66013574

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

 

Selected Recent publications

 

Tan CCS, Owen CJ, Tham CYL, Bertoletti A, van Dorp L, Balloux F. Pre-existing T cell-mediated cross-reactivity to SARS-CoV-2 cannot solely be explained by prior exposure to endemic human coronaviruses. Infect Genet Evol. 2021 Sep 9:105075. doi: 10.1016/j.meegid.2021.105075. PMID: 34509646.

 

Bertoletti A, Le Bert N, Qui M, Tan AT. SARS-CoV-2-specific T cells in infection and vaccination. Cell Mol Immunol. 2021 Sep 1:1–6. doi: 10.1038/s41423-021-00743-3. PMID: 34471260; PMCID: PMC8408362.

 

Hafezi M, Tan A, Bertoletti A. Personalized Armored TCR-Redirected T Cell Therapy for Liver/Organ Transplant with Recurrent Cancer. Cells. 2021 Jul 22;10(8):1861. doi: 10.3390/cells10081861. PMID: 34440630; PMCID: PMC8393584.

 

Lozano-Ojalvo D, Camara C, Lopez-Granados E, Nozal P, Del Pino-Molina L, Bravo-Gallego LY, Paz-Artal E, Pion M, Correa-Rocha R, Ortiz A, Lopez-Hoyos M, Iribarren ME, Portoles J, Rojo-Portoles MP, Ojeda G, Cervera I, Gonzalez-Perez M, Bodega-Mayor I, Montes-Casado M, Portoles P, Perez-Olmeda M, Oteo J, Sanchez-Tarjuelo R, Pothula V, Schwarz M, Brahmachary M, Tan AT, Le Bert N, Berin C, Bertoletti A, Guccione E, Ochando J. Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naive and COVID-19 recovered individuals. Cell Rep. 2021 Aug 24;36(8):109570. doi: 10.1016/j.celrep.2021.109570. PMID: 34390647; PMCID: PMC8332924.

 

Healy K, Pavesi A, Parrot T, Sobkowiak MJ, Reinsbach SE, Davanian H, Tan AT, Aleman S, Sandberg JK, Bertoletti A, Sällberg Chen M. Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions. JHEP Rep. 2021 Jun 11;3(4):100318. doi: 10.1016/j.jhepr.2021.100318. PMID: 34377970; PMCID: PMC8327138.

 

Mulder K, Patel AA, Kong WT, Piot C, Halitzki E, Dunsmore G, Khalilnezhad S, Irac SE, Dubuisson A, Chevrier M, Zhang XM, Tam JKC, Lim TKH, Wong RMM, Pai R, Khalil AIS, Chow PKH, Wu SZ, Al-Eryani G, Roden D, Swarbrick A, Chan JKY, Albani S, Derosa L, Zitvogel L, Sharma A, Chen J, Silvin A, Bertoletti A, Blériot C, Dutertre CA, Ginhoux F. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity. 2021 Aug 10;54(8):1883-1900.e5. doi: 10.1016/j.immuni.2021.07.007. PMID: 34331874.

 

Goletti D, Petrone L, Manissero D, Bertoletti A, Rao S, Ndunda N, Sette A, Nikolayevskyy V. The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses. Clin Microbiol Infect. 2021 Jul 10:S1198-743X(21)00378-5. doi: 10.1016/j.cmi.2021.07.005. PMID: 34256141; PMCID: PMC8272618.