Generation of multivalent genome-wide T cell responses in HLA-A*0201 transgenic mice by an HIV-1 expression library immunization (ELI) vaccine.

Rana A. Singh, Michael A Barry

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

HIV-1 is a fundamentally difficult target for vaccines because of its high mutation rate and its repertoire of immune evasion strategies. To address these difficulties, a multivalent genetic vaccine or "live genetic vaccine" was recently developed against HIV-1 using the expression library immunization (ELI) approach. In this HIV-1 vaccine, all open reading frames of HTLV-IIIb are expressed as protein fragments to retain all viral T cell epitopes, but destroy protein toxicity, inactivate immune escape functions, and reveal subdominant epitopes. In addition, each antigen fragment is fused to the ubiquitin protein to increase antigen expression and target these antigens to the proteasome to enhance cytotoxic T lymphocyte (CTL) responses. This multivalent vaccine also has the advantage of being incapable of generating infectious HIV-1 virus because of the segregation of the HIV genome into 32 separate plasmids. In this work, we demonstrate the ability of this genetic vaccine to provoke robust HLA-A*0201-restricted T cell responses in MHC class I humanized mice against gag, pol, env, and nef after a single round of immunization. In addition, this HTLV-IIIb-derived vaccine demonstrated cross-clade, envelope-specific, HLA-restricted CD8 responses against clades A, D, and E. HLA-restricted CD8 responses were generated against all 32 open reading frames encoded by the multi-plasmid genetic vaccine demonstrating that a broad repertoire of human relevant CD8 responses are provoked by this vaccine. This work supports this approach to generate multivalent T cell responses to control the highly mutable and immuno-evasive HIV-1 virus.

Original languageEnglish (US)
Pages (from-to)17-19
Number of pages3
JournalResearch initiative, treatment action : RITA
Volume8
Issue number2
StatePublished - 2003
Externally publishedYes

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Transgenic Mice
HIV-1
Immunization
Vaccines
Genome
T-Lymphocytes
Antigens
Open Reading Frames
Plasmids
Viruses
Immune Evasion
AIDS Vaccines
Proteins
T-Lymphocyte Epitopes
HLA-A*02:01 antigen
Cytotoxic T-Lymphocytes
Mutation Rate
Proteasome Endopeptidase Complex
Ubiquitin
Epitopes

Cite this

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title = "Generation of multivalent genome-wide T cell responses in HLA-A*0201 transgenic mice by an HIV-1 expression library immunization (ELI) vaccine.",
abstract = "HIV-1 is a fundamentally difficult target for vaccines because of its high mutation rate and its repertoire of immune evasion strategies. To address these difficulties, a multivalent genetic vaccine or {"}live genetic vaccine{"} was recently developed against HIV-1 using the expression library immunization (ELI) approach. In this HIV-1 vaccine, all open reading frames of HTLV-IIIb are expressed as protein fragments to retain all viral T cell epitopes, but destroy protein toxicity, inactivate immune escape functions, and reveal subdominant epitopes. In addition, each antigen fragment is fused to the ubiquitin protein to increase antigen expression and target these antigens to the proteasome to enhance cytotoxic T lymphocyte (CTL) responses. This multivalent vaccine also has the advantage of being incapable of generating infectious HIV-1 virus because of the segregation of the HIV genome into 32 separate plasmids. In this work, we demonstrate the ability of this genetic vaccine to provoke robust HLA-A*0201-restricted T cell responses in MHC class I humanized mice against gag, pol, env, and nef after a single round of immunization. In addition, this HTLV-IIIb-derived vaccine demonstrated cross-clade, envelope-specific, HLA-restricted CD8 responses against clades A, D, and E. HLA-restricted CD8 responses were generated against all 32 open reading frames encoded by the multi-plasmid genetic vaccine demonstrating that a broad repertoire of human relevant CD8 responses are provoked by this vaccine. This work supports this approach to generate multivalent T cell responses to control the highly mutable and immuno-evasive HIV-1 virus.",
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