The immunologic dominance of an epitope within a rationally designed poly-epitope vaccine is influenced by multiple...

CD4⁺ T cells are essential for inducing optimal CD8⁺ T cell and antibody-producing B cell responses and maintaining their long-term immunological memory. Therefore, CD4⁺ T cells are a critical component in HIV vaccine development. Due to enormous viral gene variation and significant human host genetic diversity, HIV vaccines may need to be custom-made for different countries.

Previously, we designed a CD4⁺ T cell vaccine based on Chinese HIV isolates and HLA-DR alleles using bioinformatics tools and predicted that 20 epitopes could cover 98.1% of the Chinese population. In vivo testing of the poly-epitope antigen in mice only activated specific T cells for some epitopes. To elucidate the mechanism of the observed differential immunogenicity, we examined poly-epitope antigen processing and presentation using in vitro and in vivo analytical methods.

Enzymatic digestion indicated that all 20 epitopes comprising the poly-epitope antigen could be liberated, but MHC II binding assays showed that neither binding affinity nor dissociation rate was associated with the magnitude of T cell immune responses elicited by each peptide epitope in vaccinated mice. Mass spectrometry analysis of MHC II-bound peptides suggested that the abundance of endogenously processed peptides bound to MHC II molecules was significantly associated with the relative immunodominance of these epitopes.

These results provide a new rationale for improving the design and testing of poly-epitope vaccines for HIV and other diseases.