Cellular immunity and genetic restriction of Influenza, Hepatitis C virus infection and Hepatitis B associated heptocellular carcinoma.

Human infections, cancer development and the course of disease are mainly influenced by T cell responses. While a robust and appropriate T cell response is beneficial to the host, a weak or inappropriate response can be ineffective or even have a detrimental effect. Numerous factors influence the quality of the T cell response to viral infections or cancer development, predominant among them being the microenvironment of the infection site, the type of cells affected and in the case of infection, the variability of the virus. By understanding the key factors required for efficient control by the T cell response in a number of different viral infections and viral associated cancers, in particular HBV associated HCC, we aim to identify targets to augment and control the immune response as a way of improving the outcome of in several important human diseases.

While my group's main focus is T cell responses, a subset of the group focus on the important anti-viral restriction factor IFITM3, which is known to restrict >15 RNA viruses including Influenza A virus, HIV and Hepatitis C virus, however the mechanism of restriction is still unknown. Little conclusive data on IFITM3 is published due to its high homology to other IFITM family members. A single nucleotide polymorphism (SNP) within IFITM3 is known to prevent its viral restriction but again the mechanism for this is unknown. This interesting protein leaves us with several unanswered questions and we aim to characterise this protein using novel reagents in order to elucidate the mechanism by which viral restriction occurs.

Influenza remains a global threat. The avian influenza H7N9 outbreak in China has a high death rate and is able to transmit from human-to-human. We recently established that people with a particular genetic variant of IFITM3-rs12252-C are six times more likely to suffer from severe influenza infection than those without. This variant gene is very rare in Northern European populations, but is common in the Chinese population. The IFITM3 protein is known to inhibit the entry of many RNA viruses including influenza virus into cells and it is assumed that the variant is unable to do this. The first aim of our program is to assess if a lower level of IFITM3 expression is responsible for this association and determine which immune signalling pathway and proteins are affected. The impact of this genetic variation on the efficacy of the seasonal influenza and live attenuated vaccinations will also be evaluated.
HBV-associated Hepatocellular Carcinoma (HCC) is one of the leading causes of death from cancer worldwide. Of the 1 million new cases of liver cancer cases globally every year, 50% are in China. The second aim is to address whether differences in HCC microenvironment modulate the quality of HCC-specific T cells and if this is affected by the presence or absence of chronic infection by HBV.
To pursue these aims, we will continue to use the cohorts established through collaborations in China and will expand to include additional cohorts in the UK and abroad. Overall, we anticipate that the two main components of our programme - to study the impact of virus restriction by IFITM3 on the nature and risk of severe influenza infection and on HCV infection, and to explore new ways of manipulating tumour associated antigen-specific (TAA) T cells in HBV-associated HCC as well as HPV and EBV associated cancers, including viral and non-viral antigens –will inform vaccine development and therapeutic intervention.