title: Degeneracy and repertoire of the human HIV-1 Gag p17(77-85) CTL response.
abstract: CD8+ CTL responses are important for the control of HIV-1 infection. The immunodominant HLA-A2-restricted Gag epitope, SLYNTVATL (SL9), is considered to be a poor immunogen because reactivity to it is rare in acute infection despite its paradoxical dominance in patients with chronic infection. We have previously reported SL9 to be a help-independent epitope in that it primes highly activated CTLs ex vivo from CD8+ T cells of seronegative healthy donors. These CTLs produce sufficient cytokines for extended autocrine proliferation but are sensitive to activation-induced cell death, which may cause them to be eliminated by a proinflammatory cytokine storm. Here we identified an agonist variant of the SL9 peptide, p41 (SLYNTVAAL), by screening a large synthetic combinatorial nonapeptide library with ex vivo-primed SL9-specific T cells. p41 invariably immunized SL9-cross-reactive CTLs from other donors ex vivo and H-2Db beta2m double knockout mice expressing a chimeric HLA-A*0201/H2-Db MHC class I molecule. Parallel human T cell cultures showed p41-specific CTLs to be less fastidious than SL9-CTLs in the level of costimulation required from APCs and the need for exogenous IL-2 to proliferate (help dependent). TCR sequencing revealed that the same clonotype can develop into either help-independent or help-dependent CTLs depending on the peptide used to activate the precursor CD8+ T cells. Although Ag-experienced SL9-T cells from two patients were also sensitive to IL-2-mediated cell death upon restimulation in vitro, the loss of SL9 T cells was minimized with p41. This study suggests that agonist sequences can replace aberrantly immunogenic native epitopes for the rational design of vaccines targeting HIV-1.
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. kanmitch@karmanos.org
authors.forename: June
authors.initials: J
authors.lastname: Kan-Mitchell
authors.forename: Melissa
authors.initials: M
authors.lastname: Bajcz
authors.forename: Keri L
authors.initials: KL
authors.lastname: Schaubert
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Tedi E
authors.initials: TE
authors.lastname: Asher
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Hwee L
authors.initials: HL
authors.lastname: Ng
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Benito
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Hegde
authors.forename: Franco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: César
authors.initials: C
authors.lastname: Boggiano
authors.forename: Dianne
authors.initials: D
authors.lastname: Wilson
authors.forename: Judith
authors.initials: J
authors.lastname: Abrams
authors.forename: Sylvie E
authors.initials: SE
authors.lastname: Blondelle
authors.forename: Darcy B
authors.initials: DB
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D045142:Cross-Priming; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D015683:Gene Products, gag / Q000276:immunology* / Q000378:metabolism; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015488:HIV Antigens / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011237:Predictive Value of Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015488:HIV Antigens; D010446:Peptide Fragments; D019151:Peptide Library; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1