Correlates of infection outcome following multiple exposures to the Hepatitis C virus
Lucas, M., Pfafferott, K., Baker, R., Cheng, W., Mollison, L., Baccala, M., Miczkova, S., Nazareth, S., Herrmann, S., Rauch, A. and Gaudieri, S. (2009) Correlates of infection outcome following multiple exposures to the Hepatitis C virus. In: 16th International Symposium on Hepatitis C Virus & Related Viruses, 3 - 7 October, Nice, France.
Exposure to HCV genotypes 1 and 3 is common but cross-protection between these two genotypes is not well understood and likely to be limited. An important correlate of HCV infection outcome is the host’s immune response and the virus’ adaptation to these responses. However, the ability to measure successful immune responses against HCV is dependent on our choice of antigenic targets relevant for different host Human Leucocyte Antigen (HLA) types. Given the bias in published HCV epitopes for a few common HLA types and genotype 1, we undertook a population-based genetic approach to identify in-vivo immune targets for HCV genotypes 1 and 3. This genetic study revealed a number of putative novel immune targets for both genotypes, but importantly only few were in common. From this list, predicted HCV epitopes were designed to examine HCV genotype immune responses (specific and cross-protective) in individuals with haemophilia who were exposed to multiple HCV genotypes via contaminated blood products. Accordingly, individuals in this cohort that remain HCV RNA-negative demonstrate the signature of a successful multi-genotype control. On the other hand, individuals that develop chronic infection may have successfully suppressed at least one genotype but are still chronically infected with another. Individualised IFN-gamma ELISpots accounting for an individual’s HLA type, HCV sequence and using the predicted epitopes (including wildtype and escape variants) were performed on 32 individuals with chronic infection and 30 individuals who had resolved infection (spontaneous/therapy). Importantly, individuals with chronic HCV infection with one genotype exhibit genotype specific T-cell responses against the alternative genotype, likely reflecting successful immune control of at least one genotype. Conclusion: The identification and functional analysis of biologically relevant genotype-specific T-cell responses in this cohort of individuals will provide critical insights for the understanding of HCV resolution in the setting of multi-genotype exposure. It will also provide the basis for the development of therapeutic strategies to combat HCV infection, including an effective vaccine directed against HCV genotypes.
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|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
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