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Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development.

ABSTRACT: With over 150 million people chronically infected worldwide and millions more infected annually, hepatitis C continues to pose a burden on the global healthcare system. The standard therapy of hepatitis C remains expensive, with severe associated side effects and inconsistent cure rates. Vaccine development against the hepatitis C virus has been hampered by practical and biological challenges posed by viral evasion mechanisms. Despite these challenges, HCV vaccine research has presented a number of candidate vaccines that progressed to phase II trials. However, those efforts focused mainly on HCV genotypes 1 and 2 as vaccine targets and barely enough attention was given to genotype 4, the variant most prevalent in the Middle East and central Africa. We describe herein the in silico identification of highly conserved and immunogenic T-cell epitopes from the HCV genotype 4 proteome, using the iVAX immunoinformatics toolkit, as targets for an epitope-driven vaccine. We also describe a fast and inexpensive approach for results validation using the empirical data on the Immune Epitope Database (IEDB) as a reference. Our analysis identified 90 HLA class I epitopes of which 20 were found to be novel and 19 more had their binding predictions retrospectively validated; empirical data for the remaining 51 epitopes was insufficient to validate their binding predictions. Our analysis also identified 14 HLA class II epitopes, of which 8 had most of their binding predictions validated. Further investigation is required regarding the efficacy of the identified epitopes as vaccine targets in populations where HCV genotype 4 is most prevalent.

SUBMITTER: Abdel-Hady KM

PROVIDER: S-EPMC4896781 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development.

Abdel-Hady Karim M KM Gutierrez Andres H AH Terry Frances F Desrosiers Joe J De Groot Anne S AS Azzazy Hassan M E HM

Human vaccines & immunotherapeutics 20140101 8

With over 150 million people chronically infected worldwide and millions more infected annually, hepatitis C continues to pose a burden on the global healthcare system. The standard therapy of hepatitis C remains expensive, with severe associated side effects and inconsistent cure rates. Vaccine development against the hepatitis C virus has been hampered by practical and biological challenges posed by viral evasion mechanisms. Despite these challenges, HCV vaccine research has presented a number ...[more]

PMID: 25424944

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Project description:The hepatitis C virus (HCV) E2 glycoprotein is a major target of the neutralizing antibody (nAb) response, with multiple type-specific and broadly neutralizing antibody (bnAb) epitopes identified. The 412-to-423 region can generate bnAbs that block interaction with the cell surface receptor CD81, with activity toward multiple HCV genotypes. In this study, we reveal the structure of rodent monoclonal antibody 24 (MAb24) with an extensive contact area toward a peptide spanning the 412-to-423 region. The crystal structure of the MAb24-peptide 412-to-423 complex reveals the paratope bound to a peptide hairpin highly similar to that observed with human MAb HCV1 and rodent MAb AP33, but with a different angle of approach. In viral outgrowth experiments, we demonstrated three distinct genotype 2a viral populations that acquired resistance to MAb24 via N415D, N417S, and N415D/H386R mutations. Importantly, the MAb24-resistant viruses exhibited significant increases in sensitivity to the majority of bnAbs directed to epitopes within the 412-to-423 region and in additional antigenic determinants located within E2 and the E1E2 complex. This study suggests that modification of N415 causes a global change in glycoprotein structure that increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.IMPORTANCE Understanding how antibodies neutralize hepatitis C virus (HCV) is essential for vaccine development. This study reveals for the first time that when HCV develops resistance to a major class of bnAbs targeting the 412-to-423 region of E2, this results in a concomitant increase in sensitivity to neutralization by a majority of other bnAb specificities. Vaccines for the prevention of HCV infection should therefore generate bnAbs directed toward the 412-to-423 region of E2 and additional bnAb epitopes within the viral glycoproteins.

Dataset Information

Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development.

Publications

Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development.

Similar Datasets

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