title: Impaired processing and presentation of cytotoxic-T-lymphocyte (CTL) epitopes are major escape mechanisms from CTL immune pressure in human immunodeficiency virus type 1 infection.
abstract: Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yokomaku
authors.forename: Hideka
authors.initials: H
authors.lastname: Miura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tomiyama
authors.forename: Ai
authors.initials: A
authors.lastname: Kawana-Tachikawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Asato
authors.initials: A
authors.lastname: Kojima
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nagai
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Zene
authors.initials: Z
authors.lastname: Matsuda
authors.forename: Koya
authors.initials: K
authors.lastname: Ariyoshi
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D015234:HLA-A Antigens / Q000737:chemistry / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: 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; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1