The immunopathogenesis of Epstein-Barr virus-associated malignancies. (360G-Wellcome-100326_Z_12_Z)

Epstein-Barr virus (EBV) infects > 90% of the human population and is associated with a broad spectrum of diseases, including an array of distinct malignancies. Indeed, EBV was first isolated from a Burkitt lymphoma tumour specimen almost 50 years ago and represents the prototype human oncogenic virus. The global burden of EBV-associated malignancies is startling, with approximately 200,000 new cases reported annually. At present, however, there are no commercially available vaccines, no effectiv e antiviral drugs and no virus-targeted therapeutics to prevent or treat these devastating malignancies. The research questions in this proposal reflect the pressing need for rational intervention in the EBV-associated oncogenic process, collectively aiming to identify pathways to prevention and cure. Novel immunotechnological approaches will be developed to profile EBV-specific T-cell immunity and reveal the immunological lesions that underlie the failure of immune surveillance in otherwise imm unocompetent individuals. These tools will also be used to monitor a poxvirus-vectored vaccine that aims to generate EBV-derived latent antigen-specific T-cell responses to correct the immune deficit and effectively target transformed B-cells. Further, novel bispecific high affinity T-cell receptor-based reagents will be developed to redirect T-cell immunity against established EBV-associated malignancies. Successful delivery and application of these cutting edge immunotechnologies and immunothe rapeutic strategies will have direct translational implications for human health.