title: The HIV-1 HLA-A2-SLYNTVATL is a help-independent CTL epitope.
abstract: The CTL response to the HLA-A*0201-restricted, HIV-1 p17 Gag(77-85) epitope (SLYNTVATL; SL9) has been extensively studied in patients. Although this reactivity is exceptionally prominent in chronically infected patients and inversely correlated to viral load, SL9-specific CTLs (SL9-CTLs) are rarely detected in acute infection. To explore the cellular basis for this unusual manifestation, SL9-CTLs primed ex vivo from naive circulating CD8(+) T cells of healthy, seronegative donors were generated and characterized. SL9 appeared to differ from other well-studied A*0201-restricted epitopes in several significant respects. In contrast to published reports for influenza and melanoma peptides and the HIV gag IV9 epitope studied here in parallel, SL9-CTLs were primed by immature but not mature autologous dendritic cells. Highly activated SL9-CTLs produce sufficient autocrine mediators to sustain clonal expansion and CTL differentiation for months without CD4(+) T cells or exogenous IL-2. Moreover, SL9-CTLs were sensitive to paracrine IL-2-induced apoptosis. IL-2 independence and sensitivity to paracrine IL-2 were also characteristic of SL9-CTLs immunized by dendritic cells transduced by a nonreplicating lentiviral vector encoding full-length Gag. In vitro-primed SL9-CTLs resembled those derived from patients in degeneracy of recognition and functional avidities for both SL9 and its natural mutations. Together, these data show that SL9 is a highly immunogenic, help-independent HIV epitope. The scarcity of SL9-CTLs in acute infection may result from cytokine-induced apoptosis with the intense activation of the innate immunity. In contrast, SL9-CTLs that constitutively produce autocrine help would predominate during CD4-diminished chronic infection.
authors.affiliation: Karmanos Cancer Institute, Department of Pathology and Immunology, Wayne State University, Detroit, MI 48201, USA. kanmitch@karamanos.org
authors.forename: June
authors.initials: J
authors.lastname: Kan-Mitchell
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Keri L
authors.initials: KL
authors.lastname: Schaubert
authors.forename: Melissa
authors.initials: M
authors.lastname: Bajcz
authors.forename: Michal
authors.initials: M
authors.lastname: Bereta
mesh_terms: D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000502:physiology; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015683:Gene Products, gag / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta; D005822:Genetic Vectors; D015488:HIV Antigens / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D009154:Mutation; D019899:Paracrine Communication / Q000276:immunology; D010446:Peptide Fragments; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015488:HIV Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D010446:Peptide Fragments; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; C473991:p17 gag peptide, human immunodeficiency virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1