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.