Optimization and immune recognition of multiple novel conserved HLA-A2, human immunodeficiency virus type 1-specific CTL epitopes

• Published in: Journal of general virology 2003-09, Vol.84 (9), p.2409-2421
• Main Authors: Corbet, Sylvie, Nielsen, Henrik Vedel, Vinner, Lasse, Lauemoller, Sanne, Therrien, Dominic, Tang, Sheila, Kronborg, Gitte, Mathiesen, Lars, Chaplin, Paul, Brunak, Soren, Buus, Soren, Fomsgaard, Anders
• Format: Article
• Language: English
• Subjects: Adult; Animals; CD8-Positive T-Lymphocytes - immunology; Epitopes, T-Lymphocyte; Female; Gene Products, rev - immunology; Gene Products, vif - immunology; HIV Infections - blood; HIV Infections - immunology; HIV-1 - chemistry; HIV-1 - immunology; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Human immunodeficiency virus 1; Human Immunodeficiency Virus Proteins; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Oligopeptides - analysis; rev Gene Products, Human Immunodeficiency Virus; Species Specificity; T-Lymphocytes, Cytotoxic - immunology; vif Gene Products, Human Immunodeficiency Virus; Viral Regulatory and Accessory Proteins - immunology
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.19152-0

1 Department of Virology, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark 2 Institute for Medical Microbiology and Immunology, University of Copenhagen, Denmark 3 Department of Infectious Diseases, University Hospital of Copenhagen, Denmark 4 Department of Infectious Diseases, University Hospital of Hvidovre, Denmark 5 Bavarian Nordic Research Institute, Martinsried, Germany 6 Center for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark, Lyngby, Denmark Correspondence Anders Fomsgaard afo{at}ssi.dk MHC-I-restricted cytotoxic responses are considered a critical component of protective immunity against viruses, including human immunodeficiency virus type 1 (HIV-1). CTLs directed against accessory and early regulatory HIV-1 proteins might be particularly effective; however, CTL epitopes in these proteins are rarely found. Novel artificial neural networks (ANNs) were used to quantitatively predict HLA-A2-binding CTL epitope peptides from publicly available full-length HIV-1 protein sequences. Epitopes were selected based on their novelty, predicted HLA-A2-binding affinity and conservation among HIV-1 strains. HLA-A2 binding was validated experimentally and binders were tested for their ability to induce CTL and IFN- responses. About 69 % were immunogenic in HLA-A2 transgenic mice and 61 % were recognized by CD8 + T-cells from 17 HLA-A2 HIV-1-positive patients. Thus, 31 novel conserved CTL epitopes were identified in eight HIV-1 proteins, including the first HLA-A2 minimal epitopes ever reported in the accessory and regulatory proteins Vif, Vpu and Rev. Interestingly, intermediate-binding peptides of low or no immunogenicity (i.e. subdominant epitopes) were found to be antigenic and more conserved. Such epitope peptides were anchor-optimized to improve immunogenicity and further increase the number of potential vaccine epitopes. About 67 % of anchor-optimized vaccine epitopes induced immune responses against the corresponding non-immunogenic naturally occurring epitopes. This study demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple anchor-optimized variants of the more conserved subdominant epitopes.