title: Generation of genome-wide CD8 T cell responses in HLA-A*0201 transgenic mice by an HIV-1 ubiquitin expression library immunization vaccine.
abstract: HIV-1 is a fundamentally difficult target for vaccines due to its high mutation rate and its repertoire of immunoevasive strategies. To address these difficulties, a multivalent, proteasome-targeted, live genetic vaccine was recently developed against HIV-1 using the expression library immunization approach. In this HIV-1 vaccine all open reading frames of HIV-1 are expressed from 32 plasmids as Ag fragments fused to the ubiquitin protein to increase Ag targeting to the proteasome to enhance CTL responses. In this work we demonstrate the ability of the HIV-1 library vaccine to simultaneously provoke robust HLA-A*0201-restricted T cell responses against all 32 HIV-1 library vaccine Ags after single immunization by gene gun. These CD8 T cell responses included HLA-A*0201-restricted CTL activity, CD8/IFN-gamma T cell responses, and HLA tetramer binding against defined immunodominant epitopes in gag, pol, env, and nef as well as potent CD8/IFN-gamma responses against undefined HLA-A*0201-restricted epitopes in all remaining Ags of the library. CD8 responses mediated by single gag, pol, env, and nef plasmids from the vaccine demonstrated little reduction in specific T cell responses when these plasmids were diluted into the context of the full 32-plasmid library, suggesting that Ag dominance or immune interference is not an overt problem to limit the efficacy of this complex vaccine. Therefore, this work demonstrates the ability of the HIV-1 library vaccine to generate robust multivalent genome-wide T cell responses as one approach to control the highly mutable and immunoevasive HIV-1 virus.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Rana A K
authors.initials: RA
authors.lastname: Singh
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015684:Gene Products, pol / Q000235:genetics / Q000276:immunology; D015698:Genomic Library; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000502:physiology; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D054302:pol Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D015684:Gene Products, pol; D015488:HIV Antigens; D016655:HIV Core Protein p24; C060467:HIV pol protein p65; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D054302:pol Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma