AEGiS-15IAC: Deletion of an immunodominant epitope induces subdominant epitope-specific CTL responses in a limited range.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Deletion of an immunodominant epitope induces subdominant epitope-specific CTL responses in a limited range.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. ThOrA1391)

Im EJ, McMichael AJ, Hanke T
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, University of Oxford, Oxford, United Kingdom

BACKGROUND: The aim for an effective CTL-based HIV vaccine is the induction of broad CTL responses to reduce the chance of virus escaping recognition by our immune defense systems. However, immunodominance causes T cells to focus mainly on small numbers of dominant epitopes, rendering the majority of the other epitopes ineffective.<IMG SRC="images/prog/ThOrA1391_IMG01.jpg" border=0>

METHODS: A candidate HIV clade A vaccine, HIVA, targeted for phase III efficacy trials in central and eastern Africa, has been constructed by our lab and is currently being evaluated in phase II clinical trials. HIVA is based on the p17/p24 gag region and a string of CTL epitopes. The immunodominant epitope P18-I10 which was included in the immunogen as a pre-clinical evaluation marker for BALB/c, was deleted and named HIVAdP18-I10. Groups of BALB/c mice were immunized in a prime-boost regimen with DNA and MVA expressing HIVA or HIVAdP18-I10. CD8 T cell responses were detected using IFNgamma ELISPOT, MHC class I tetramer, intracellular cytokine staining and 51chromium release assays.

RESULTS: Significant increase of the subdominant epitope G1(gag)-specific CD8 T cell responses were detected after deletion of the immunodominant epitope P18-I10. However, T cell responses directed against the second subdominant epitope G2 (gag) were still undetectable despite the absence of immunodominant epitope P18-I10. Conclusion Immunodominance is known to occur between different MHC class I restricted epitopes. The deletion of a dominant epitope initially thought to be able to induce responses to most of the subdominant epitopes resulted in eliciting CTL responses only to the next dominant epitope. This implies that overcoming immunodominance may be more complex than previously envisaged. Further charaterization by serial deletion of CTL epitopes in their order of immunodominance hierarchy will need to be studied to clearly elucidate a plausible mechanism for the immunodominance observed.

Keywords: AEGIS, Immunodominant Epitopes, Epitopes, CD8-Positive T-Lymphocytes, AIDS Vaccines, T-Lymphocytes, Africa, Eastern, Animal, Mice, immunology

040711
ThOrA1391