Role of cytotoxic T-lymphocyte-mediated immune selection in a dominant human leukocyte antigen-B8-restricted cytotoxic T-lymphocyte epitope in Nef.
OBJECTIVE
To study the role of cytotoxic T-lymphocyte (CTL) escape for disease progression in HIV-1 infection, we analyzed the CTL response to the dominant human leukocyte antigen (HLA)-B8-restricted CTL epitope FLKEKGGL (FL8) in HIV-1 Nef.


METHODS
HIV-1 nef genes derived from 56 patients were analyzed by polymerase chain reaction (PCR)-based sequencing. T-cell responses against FL8 and mutated FL8 variants were detected by gamma-interferon (gamma-IFN) enzyme linked immunospot (ELISPOT) assay.


RESULTS
The longitudinal analysis of an HIV-1-infected patient with good control of HIV-1 viremia for several years demonstrated an association of rising viremia with the emergence of CTL escape mutations within the HLA-B8-restricted Nef-specific CTL epitopes FLKEKGGL and WPAIRERM. Analysis of nef genes in 56 HIV-1-infected patients demonstrated a significant correlation between the occurrence of mutations in the FL8 epitope and the presence of HLA-B8. The mutations within the FL8 epitope could decrease CTL recognition; however, there was strong variation regarding the recognition of viral variants between individual donors. The presence of FL8 mutations was associated with lower CD4 cell counts and higher viral loads.


CONCLUSIONS
Our data demonstrate a strong CTL selection pressure on the immunodominant HLA-B8-restricted CTL epitope FL8 in HIV-1 Nef. The association of FL8 mutations with lower CD4 cell counts indicates an important role of CTL escape mutations for disease progression.
Maurer
Katja
K
Department of Internal Medicine 3, University Erlangen-Nuremberg, Germany.
Harrer
Ellen G
EG
Goldwich
Andreas
A
Eismann
Kathrin
K
Bergmann
Silke
S
Schmitt-Haendle
Matthias
M
Spriewald
Bernd
B
Mueller
Sandra M
SM
Harrer
Thomas
T
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D018984:Epitopes, T-Lymphocyte; D005260:Female; D015795:HLA-B8 Antigen / Q000032:analysis / Q000502:physiology*; D006801:Humans; D016056:Immunodominant Epitopes; D008137:Longitudinal Studies; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015795:HLA-B8 Antigen; D016056:Immunodominant Epitopes; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1