title: Cross-reactive cytotoxic T lymphocytes against human immunodeficiency virus type 1 protease and gamma interferon-inducible protein 30.
abstract: The gamma interferon (IFN-gamma)-inducible protein 30 (IP-30) signal peptide -11 to -3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-gamma, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-gamma. Neither high levels of exogenous IFN-gamma nor incubation of PBMC with other HIV peptides triggering substantial IFN-gamma release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-gamma release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-gamma release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide -11 to -3, which has implications for immune memory and autoimmunity.
authors.affiliation: H1809 Immunology-Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland, Canada A1B 3V6.
authors.forename: R D
authors.initials: RD
authors.lastname: Mason
authors.forename: M I
authors.initials: MI
authors.lastname: Bowmer
authors.forename: C M
authors.initials: CM
authors.lastname: Howley
authors.forename: M D
authors.initials: MD
authors.lastname: Grant
mesh_terms: D002478:Cells, Cultured; D003429:Cross Reactions; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D016333:HIV Protease / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear; D010088:Oxidoreductases / Q000276:immunology*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015789:HLA-A2 Antigen; D010455:Peptides; D007371:Interferon-gamma; D010088:Oxidoreductases; C056859:IFI30 protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors; D016333:HIV Protease