Sequence conservation of subdominant HLA-A2-binding CTL epitopes in HIV-1 clinical isolates and CD8+ T-lymphocyte cross-recognition may explain the immune reaction in infected individuals
Cytotoxic T-lymphocytes (CTL) are critical for immune control of infection with human immunodeficiency virus type-1 (HIV-1) and searches for relevant CTL epitopes for immune therapy are ongoing. Recently, we identified 28 HLA-A2-binding HIV-1 CTL epitopes (1). In this follow-up study we fully genome sequenced HIV-1 from 11 HLA-A2+ patients to examine the sequence variation of these natural epitopes and compared them with the patient's CD8+ T-cell recall response. Often the epitope was conserved but only a few patients showed a CD8+ T-cell recall response. This infrequent targeting may be explained by immune subdominance. CD8+ T-cell recall response to a natural epitope could be measured despite sequence differences in the patient's virus. T-cell cross-reaction between such variants could be demonstrated in HLA-A2 transgenic mice. Nine infrequently targeted but conserved or cross-reacting epitopes were identified in seven HIV-1 proteins. More immunogenic anchor amino acid optimized immunogens were designed that induced T-cell cross-reaction with these natural epitopes. It is concluded that most of the new CTL epitopes are conserved but subdominant during the infection. It is suggested that T-cell promiscuity may explain the observed CD8+ T-cell reaction to epitope variants and it may be possible to use the selected immune optimized epitope peptides for therapeutic vaccination.
Document Type: Research Article
Affiliations: 1: Department of Virology, Statens Serum Institut, Copenhagen, 2: Department of Infectious Diseases, University Hospital of Hvidovre, Hvidovre, and 3: Department of Infectious Diseases, University Hospital of Copenhagen, Denmark
Publication date: 01 June 2007