Design, Expression, and Processing of Epitomized Hepatitis C Virus-Encoded CTL Epitopes1

Hepatitis C virus (HCV) vaccine efficacy may crucially depend on immunogen length and coverage of viral sequence diversity. However, covering a considerable proportion of the circulating viral sequence variants would likely require long immunogens, which for the conserved portions of the viral genome, would contain unnecessarily redundant sequence information. In this study, we present the design and in vitro performance analysis of a novel “epitome” approach that compresses frequent immune targets of the cellular immune response against HCV into a shorter immunogen sequence. Compression of immunological information is achieved by partial overlapping shared sequence motifs between individual epitopes. At the same time, sequence diversity coverage is provided by taking advantage of emerging cross-reactivity patterns among epitope variants so that epitope variants associated with the broadest variant cross-recognition are preferentially included. The processing and presentation analysis of specific epitopes included in such a compressed, in vitro-expressed HCV epitome indicated effective processing of a majority of tested epitopes, although re-presentation of some epitopes may require refined sequence design. Together, the present study establishes the epitome approach as a potential powerful tool for vaccine immunogen design, especially suitable for the induction of cellular immune responses against highly variable pathogens.

[1]  Todd M. Allen,et al.  Increased detection of HIV-specific T cell responses by combination of central sequences with comparable immunogenicity , 2008, AIDS.

[2]  Todd M. Allen,et al.  Increased Cytotoxic T-Lymphocyte Epitope Variant Cross-Recognition and Functional Avidity Are Associated with Hepatitis C Virus Clearance , 2008, Journal of Virology.

[3]  Todd M. Allen,et al.  Increased Sequence Diversity Coverage Improves Detection of HIV-Specific T Cell Responses1 , 2007, The Journal of Immunology.

[4]  B. Walker,et al.  Portable flanking sequences modulate CTL epitope processing. , 2007, The Journal of clinical investigation.

[5]  Nebojsa Jojic,et al.  Extensive HLA class I allele promiscuity among viral CTL epitopes , 2007, European journal of immunology.

[6]  P. Doherty,et al.  The Context of Epitope Presentation Can Influence Functional Quality of Recalled Influenza A Virus-Specific Memory CD8+ T Cells1 , 2007, The Journal of Immunology.

[7]  Raymond T Chung,et al.  Human leukocyte antigen–associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution , 2007, Hepatology.

[8]  F. Lemonnier,et al.  A polyepitope DNA vaccine targeted to Her-2/ErbB-2 elicits a broad range of human and murine CTL effectors to protect against tumor challenge. , 2007, Cancer research.

[9]  David Heckerman,et al.  Coping with Viral Diversity in HIV Vaccine Design , 2007, PLoS Comput. Biol..

[10]  C. Brander,et al.  Lytic and Latent Antigens of the Human Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Induce T-Cell Responses with Similar Functional Properties and Memory Phenotypes , 2007, Journal of Virology.

[11]  David Heckerman,et al.  CD8+ T-cell responses to different HIV proteins have discordant associations with viral load , 2007, Nature Medicine.

[12]  Todd M. Allen,et al.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection , 2006, PLoS medicine.

[13]  F. Bihl,et al.  Targets of emerging therapies for viral hepatitis B and C , 2006, Expert opinion on therapeutic targets.

[14]  S. Green,et al.  Dengue Virus-Reactive CD8+ T Cells Display Quantitative and Qualitative Differences in Their Response to Variant Epitopes of Heterologous Viral Serotypes1 , 2006, The Journal of Immunology.

[15]  David Heckerman,et al.  Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes , 2006, Nature Immunology.

[16]  Brendan J. Frey,et al.  Using ``epitomes'' to model genetic diversity: Rational design of HIV vaccine cocktails , 2005, NIPS 2005.

[17]  C. Brander,et al.  Simultaneous assessment of cytotoxic T lymphocyte responses against multiple viral infections by combined usage of optimal epitope matrices, anti- CD3 mAb T-cell expansion and "RecycleSpot" , 2005, Journal of Translational Medicine.

[18]  J. Sidney,et al.  Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag77–85 , 2005, European journal of immunology.

[19]  Todd M. Allen,et al.  CD8 Epitope Escape and Reversion in Acute HCV Infection , 2004, The Journal of experimental medicine.

[20]  Bette Korber,et al.  Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA , 2004, Nature.

[21]  Todd M. Allen,et al.  High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. , 2004, Gastroenterology.

[22]  P. Kloetzel,et al.  Hepatitis C virus mutation affects proteasomal epitope processing. , 2004, The Journal of clinical investigation.

[23]  Edward C. Holmes,et al.  High-Resolution Phylogenetic Analysis of Hepatitis C Virus Adaptation and Its Relationship to Disease Progression , 2004, Journal of Virology.

[24]  F. M. Marincola,et al.  Consistent Cytotoxic-T-Lymphocyte Targeting of Immunodominant Regions in Human Immunodeficiency Virus across Multiple Ethnicities , 2004, Journal of Virology.

[25]  S. Emerson,et al.  In vitro assay for neutralizing antibody to hepatitis C virus: Evidence for broadly conserved neutralization epitopes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Charles M. Rice,et al.  HCV Persistence and Immune Evasion in the Absence of Memory T Cell Help , 2003, Science.

[27]  Todd M. Allen,et al.  Enhanced Detection of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses to Highly Variable Regions by Using Peptides Based on Autologous Virus Sequences , 2003, Journal of Virology.

[28]  J. Ghrayeb,et al.  Memory CD8+ T Cells Are Required for Protection from Persistent Hepatitis C Virus Infection , 2003, The Journal of experimental medicine.

[29]  Søren Brunak,et al.  Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation , 2002, Journal of Virology.

[30]  J Alexander,et al.  Optimizing vaccine design for cellular processing, MHC binding and TCR recognition. , 2002, Tissue antigens.

[31]  B. Walker,et al.  Cellular immune responses against hepatitis C virus: the evidence base 2002 , 2002, Clinical and experimental immunology.

[32]  K. Cao,et al.  Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. , 2001, Human immunology.

[33]  E. Rosenberg,et al.  Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children , 2000, Journal of Virology.

[34]  H J Alter,et al.  The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. , 2000, Science.

[35]  O. Weiland,et al.  Limited humoral immunity in hepatitis C virus infection. , 1999, Gastroenterology.

[36]  A. Sette,et al.  Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. , 1997, The Journal of clinical investigation.