title: Heteroclitic Peptides Increase Proliferation and Reduce Evidence of Human Immunodeficiency Virus-Specific CD8⁺ T Cell Dysfunction.
abstract: Human immunodeficiency virus (HIV)-specific CD8(+) T cell dysfunction parallels disease progression; therefore, restoring potent HIV-specific CD8(+) T cell responses is a key therapeutic goal. Certain CD8(+) T cell peptide epitope variants, termed heteroclitic, enhance cytokine production by the HIV-specific CD8(+) T cells of some individuals. In this study, we investigated whether heteroclitic peptides that enhance cytokine production by HIV-specific CD8(+) T cells also reduce functional and phenotypic evidence of HIV-specific CD8(+) T cell exhaustion in those instances. Twenty-four variant peptides of human histocompatibility-linked leukocyte antigen (HLA)-A2-restricted reference HIV peptide epitopes designated as A2-7; Nef 83→91, A2-8; Nef 135→143, A2-Gag; Gag 77→85 and A2-9; Gag 433→440 were synthesized with conservative and semiconservative amino acid substitutions at positions 3, 5, and 7 or 3, 5, and 8 of Gag 433→440. Variants that enhanced interferon-gamma (IFN-γ) and/or interleukin-2 (IL-2) production in enzyme-linked immunospot assays (29 cases overall) were subsequently tested by 7-day in vitro peptide stimulation for their effects on HIV-specific CD8(+) T cell proliferation and programmed death-1 (PD-1) expression. Heteroclitic variants enhanced HIV-specific CD8(+) T cell proliferation by >20% in 13/29 cases tested, reduced PD-1 expression on proliferating cells by 15-50% in 10 cases, and reduced PD-1 expression on proliferating cells by >50% in 3 cases. In five cases, the same heteroclitic peptide increased proliferation by >20% and reduced PD-1 expression by >15%. These data demonstrate that heteroclitic peptides can alter the magnitude and character of HIV-specific CD8(+) cell responses relative to reference peptides and may have a unique immunotherapeutic value in therapeutic vaccines.
authors.affiliation: Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador, Canada .
authors.forename: Adeolu
authors.initials: A
authors.lastname: Adegoke
authors.affiliation: Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador, Canada .
authors.forename: Krista
authors.initials: K
authors.lastname: Gladney
authors.affiliation: Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador, Canada .
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland , St. John's, Newfoundland and Labrador, Canada .
authors.forename: Michael
authors.initials: M
authors.lastname: Grant
mesh_terms: D019943:Amino Acid Substitution; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D006678:HIV / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D014838:Volunteers; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D050505:Mutant Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma