title: Distinct HIV-1 escape patterns selected by cytotoxic T cells with identical epitope specificity.
abstract: Pol283-8-specific, HLA-B*51:01-restricted, cytotoxic T cells (CTLs) play a critical role in the long-term control of HIV-1 infection. However, these CTLs select for the reverse transcriptase (RT) I135X escape mutation, which may be accumulating in circulating HIV-1 sequences. We investigated the selection of the I135X mutation by CTLs specific for the same epitope but restricted by HLA-B*52:01. We found that Pol283-8-specific, HLA-B*52:01-restricted CTLs were elicited predominantly in chronically HIV-1-infected individuals. These CTLs had a strong ability to suppress the replication of wild-type HIV-1, though this ability was weaker than that of HLA-B*51:01-restricted CTLs. The crystal structure of the HLA-B*52:01-Pol283-8 peptide complex provided clear evidence that HLA-B*52:01 presents the peptide similarly to HLA-B*51:01, ensuring the cross-presentation of this epitope by both alleles. Population level analyses revealed a strong association of HLA-B*51:01 with the I135T mutant and a relatively weaker association of HLA-B*52:01 with several I135X mutants in both Japanese and predominantly Caucasian cohorts. An in vitro viral suppression assay revealed that the HLA-B*52:01-restricted CTLs failed to suppress the replication of the I135X mutant viruses, indicating the selection of these mutants by the CTLs. These results suggest that the different pattern of I135X mutant selection may have resulted from the difference between these two CTLs in the ability to suppress HIV-1 replication.
authors.affiliation: Center for AIDS Research, Kumamoto University, Chuo-ku, Kumamoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yagita
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chikata
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Hayato
authors.initials: H
authors.lastname: Murakoshi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Akahoshi
authors.forename: Nico
authors.initials: N
authors.lastname: Pfeifer
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Toyoyuki
authors.initials: T
authors.lastname: Ose
authors.forename: Haruki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Ryo
authors.initials: R
authors.lastname: Kanda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Honda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawashima
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ariumi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D044466:Asian People; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D059949:HLA-B51 Antigen / Q000276:immunology / Q000378:metabolism; D059950:HLA-B52 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D044465:White People
chemical_list: D018984:Epitopes, T-Lymphocyte; C469675:HLA-B*51:01:02 antigen; C501279:HLA-B*52:01 antigen; D059949:HLA-B51 Antigen; D059950:HLA-B52 Antigen; D050505:Mutant Proteins; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase