The Mechanisms of Viral Escape in Murine and Human Influenza Infection
CD8+ T cells play a critical role in the control of virus infections. In influenza, CD8+ T cell-mediated cross-protection against different viral strains might, in the face of a pandemic, ameliorate the disease sufficiently to promote survival rather than death. However, the resultant CD8+ T cell responses exert selective pressure on viruses, leading to the possibility of escape mutations in viral peptides. Virus escape mutants constitute a major problem for CD8+ T cell-mediated control and vaccine design in persistent (LCMV, HIV, HCV, HBV, SIV) and acute (influenza) infections. To date, the extent of viral escape within influenza T cell epitopes (mutations occur in 71.4% of human T cell epitopes) has not received much attention. In seasonal influenza infection, escape from existing CD8+ T cell responses is particularly relevant to persistence of the virus within the population. In the face of a pandemic, it would lead to a total lack of CD8+ T cell cross-protection in individuals with specific HLA alleles. Thus, it is critical to understand the mechanisms of viral escape in influenza and investigate any possible compensatory strategies. Our research aims to provide insights into the CD8+ T cell escape mutants that can emerge in RNA virus infections, with the ultimate aim of improving vaccine design. We investigate mechanisms of viral escape in an easily manipulated mouse model of influenza infection, and further verify the key findings in humanised transgenic HLA-A2 mice and human peripheral blood mononuclear cells. A combination of sophisticated cellular and molecular immune assays, access to the WHO Centre database of 30,000 human influenza isolates and structural studies will help us to understand:
- the emergence of influenza viral variants
- the availability/efficacy of CD8+ T cells to recognise the emerging mutants
- any structural constraints that may limit (1) & (2).
This work will enhance our understanding of the mechanisms underlying viral escape that are critical for T cell-based protective immunity and vaccine design against influenza, persistent virus infections and tumours.
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