title: Superimposed epitopes restricted by the same HLA molecule drive distinct HIV-specific CD8+ T cell repertoires.
abstract: Superimposed epitopes, in which a shorter epitope is embedded within a longer one, can be presented by the same HLA class I molecule. CD8(+) CTL responses against such epitopes and the contribution of this phenomenon to immune control are poorly characterized. In this study, we examined HLA-A*24:02-restricted CTLs specific for the superimposed HIV Nef epitopes RYPLTFGWCF (RF10) and RYPLTFGW (RW8). Unexpectedly, RF10-specific and RW8-specific CTLs from HIV-1-infected HLA-A*24:02+ individuals had no overlapping Ag reactivity or clonotypic compositions. Single-cell TCR sequence analyses demonstrated that RF10-specific T cells had a more diverse TCR repertoire than did RW8-specific T cells. Furthermore, RF10-specific CTLs presented a higher Ag sensitivity and HIV suppressive capacity compared with RW8-specific CTLs. Crystallographic analyses revealed important structural differences between RF10- and RW8-HLA-A*24:02 complexes as well, with featured and featureless conformations, respectively, providing an explanation for the induction of distinct T cell responses against these epitopes. The present study shows that a single viral sequence containing superimposed epitopes restricted by the same HLA molecule could elicit distinct CD8+ T cell responses, therefore enhancing the control of HIV replication. This study also showed that a featured epitope (e.g., RF10) could drive the induction of T cells with high TCR diversity and affinity.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; INSERM, Unité Mixte de Recherche 1135, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Centre d'Immunologie et des Maladies Infectieuses-Paris, 75013, Paris, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China;
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; and.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; masafumi@kumamoto-u.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D059871:HLA-A24 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D011948:Receptors, Antigen, T-Cell; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1