Final Report Summary - CMVAGSTIMULUS (Molecular mechanisms of persistent antigenic stimulation in cytomegalovirus infection)
The ERC project CMVAgSTIMULUS has identified a critical role for the context of gene-expression of an antigenic determinant in the induction of inflationary responses (Dekhtiarenko et al. J. Immunol 2013). Furthermore, the project showed that antigen competition exert a substantial effect for the selection of inflationary responses (Dekhtiarenko et al. J. Immunol 2013). Detailed characterization showed that even the epitope localization within a defined protein plays a critical role in the induction of inflationary responses, because only epitopes that are accessible to the constitutive proteasome may be presented on the surface of latently infected somatic cells. This insight was utilized to test the idea that MCMV-based recombinants may provide better immune protection if an epitope is introduced onto the C-terminus of a viral protein, rather than by MCMVs expressing the full-length native protein. Both the CD8 T-cell responses and the immune protection against a challenge with tumor cells or viruses showed that epitopes expressed on the C-terminus, and thus easily accessible for proteasomal degradation, are superior immunogens to full-length proteins (Dekhtiarenko et al. PLOS Pathogen, in press). Finally, we also showed that these effects are not restricted to the artificial model of intraperitoneal infection, because they could also be observed by mucosal intranasal infection, reflecting a likely natural route of CMV infection (Oduro et al. J. Gen. Virol. 2016).