title: De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection.
abstract: Human immunodeficiency virus type 1 (HIV-1) evades CD8(+) T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8(+) T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8(+) T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8(+) T cells, four of which underwent mutation associated with dramatic loss of the original CD8(+) response. However, following the G(357)S escape in the HLA-A11-restricted Gag(349-359) epitope and the decline of wild-type-specific CD8(+) T-cell responses, a novel CD8(+) T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8(+) T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vbeta repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G(357)S escape variant of the Gag(349-359) epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8(+) T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8(+) T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, Boston, 02129, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Kalife
authors.forename: Laura L
authors.initials: LL
authors.lastname: Reyor
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Michael
authors.initials: M
authors.lastname: Cheng
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Allgaier
authors.forename: Stanley
authors.initials: S
authors.lastname: Mui
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: Nancy V
authors.initials: NV
authors.lastname: Brown
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000378:metabolism; D059870:HLA-A11 Antigen; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta