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HCV-specific T-cell responses reflect Hepatitis C infection outcome following multiple exposures to the virus

Lucas, M., Pfafferott, K., Baker, R., Baccala, M., Herrmann, S. and Gaudieri, S. (2009) HCV-specific T-cell responses reflect Hepatitis C infection outcome following multiple exposures to the virus. In: Australian Centre for HIV & Hepatitis Virology Research (ACH2) 5th National Workshop, 3 - 5 June, Terrigal, NSW, Australia.

Abstract

Background: Individuals with haemophilia were exposed to the Hepatitis C virus (HCV) via contaminated clotting factor concentrate and blood products prior to HCV screening in Australia with divergent infection outcomes from clearance of the virus to chronic infection. These individuals are likely to have been exposed to multiple HCV strains, including the major circulating HCV genotypes 1 and 3. Hence, individuals that remain persistently HCV RNA-negative despite multiple HCV exposures will demonstrate the signature of a successful multi-genotype response. Furthermore, individuals that develop chronic infection may have successfully suppressed at least one genotype but be chronically infected with another. Several studies have shown that the major determinants of outcome following infection with HCV are cellular immune responses mediated by both CD4+ and CD8+ T-cells and viral escape from these immune responses. Our previous population-based genetic study of HCV genotype 1 and 3 identified limited overlap in the immune targets within the two viral genomes. These results suggest that the immune targets within the HCV selected by the host will to a certain extent determine infection outcome following multiple HCV exposure.

Methods: Blood collection from 62 individuals with Haemophilia from the Western Australia Haemophilia Centre, of which 30 have cleared HCV (spontaneous/therapy). HLA typing of all individuals was performed using sequence-based methods. Viral sequence has been obtained (where possible) for the NS2-NS5B region. All individuals were screened using individualised IFN-gamma ELISpot assays to detect T-cell responses against genotype 1 and 3 peptides. These peptide sets are the predicted optimal peptides based on leads obtained from our genetic study described above. This novel approach takes the HLA and viral sequence of the individual into account and includes (wildtype and mutant) peptides derived from an Australian consensus sequence. This method circumvents some of the limitations of other ELIspot assays using overlapping peptides based on a laboratory reference.

Results: We were able to detect the long-term maintenance of memory T-cell responses in individuals exposed to HCV more than 15 years ago. Furthermore, individuals who are chronically infected with HCV genotype 1 or 3 show responses to peptides of an alternate genotype. Given that the genotype 1 and 3 peptide sets are largely non-overlapping, these results suggest that many of the strong immune responses we are likely to detect in individuals with chronic infection will be against those genotypes these individuals have previously cleared.

Discussion: The identification and functional analysis of biologically relevant T-cell responses in this cohort of individuals with multiple exposures to HCV will provide critical insights for the development of therapeutic strategies to combat HCV infection, including an effective vaccine directed against the primary circulating HCV genotypes in Australia.

Publication Type: Conference Item
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
URI: http://researchrepository.murdoch.edu.au/id/eprint/9398
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