De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection.
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.
Allen
Todd M
TM
Partners AIDS Research Center, Massachusetts General Hospital, Boston, 02129, USA.
Yu
Xu G
XG
Kalife
Elizabeth T
ET
Reyor
Laura L
LL
Lichterfeld
Mathias
M
John
Mina
M
Cheng
Michael
M
Allgaier
Rachel L
RL
Mui
Stanley
S
Frahm
Nicole
N
Alter
Galit
G
Brown
Nancy V
NV
Johnston
Mary N
MN
Rosenberg
Eric S
ES
Mallal
Simon A
SA
Brander
Christian
C
Walker
Bruce D
BD
Altfeld
Marcus
M
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*
D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta