Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses.
HLA-B57 has been shown to be strongly associated with slow disease progression in human immunodeficiency virus type 1 (HIV-1)-infected patients from the Amsterdam Cohort. Since HIV-1-specific CTL can control and eliminate virus-infected cells, we sought to characterize the dominant HLA-B57-restricted CTL responses at the epitope level. It was found that HLA-B57-restricted CTL responses were targeted at multiple proteins of HIV-1, with CTL specific for Gag and RT being the most pronounced. Gag-specific CTL recognized peptides ISPRTLNAW (aa 147-155) and STLQEQIGW (aa 241-249), which had previously been reported as HLA-B57-restricted. The RT-specific CTL response in one long-term survivor studied in great detail persisted for > 10 years and was dominated by HLA-B57-restricted CTL that recognized the newly defined epitope IVLPEKDSW (RT(LAI), aa 244-252). This epitope could be recognized in the context of both HLA-B*5701 and HLA-B*5801. Interestingly, three epitope variants of IVLPEKDSW were observed, which coincided with the strongest detectable CTL response to RT. One variant (T2E7) was not recognized by IVLPEKDSW-specific CTL despite the fact that this variant bound to HLA-B*5701 with a similar affinity as the index peptide. Finally, only viruses which contained the epitope index sequence were obtained suggesting efficient virus control by CTL. In conclusion, we report the characterization of dominant HIV-1 Gag- and RT-derived, HLA-B57-restricted CTL epitopes which are associated with longer time to AIDS. Further characterization of CTL responses restricted by HLA-B57 and other protective HLA alleles may contribute to the development of effective AIDS vaccines.
Klein
M R
MR
Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, and University of Amsterdam.
van der Burg
S H
SH
Hovenkamp
E
E
Holwerda
A M
AM
Drijfhout
J W
JW
Melief
C J
CJ
Miedema
F
F
D000483:Alleles; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation; D015488:HIV Antigens / Q000235:genetics; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics; D066298:In Vitro Techniques; D008137:Longitudinal Studies; D008297:Male; D009426:Netherlands; D017741:Survivors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015683:Gene Products, gag; D015488:HIV Antigens; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D016056:Immunodominant Epitopes; D054303:HIV Reverse Transcriptase