Induction of Nef-resistant HIV-1-specific CTL responses as a new strategy for the development of HIV-1-specific therapeutic vaccines
As cure of HIV-1 infection requires the eradication of viral reservoirs, cure strategies should include boosting of cytotoxic T lymphocytes (CTL) to eliminate infected cells. HIV-1 can evade CTL recognition by Nef-mediated down-regulation of HLA-A/B-expression and Vpu-mediated downregulation of HLA-C. This could explain the failure of T cell-based vaccines to prevent HIV‑1 infection and to improve control of viremia. The negative effect of Nef on CTL epitope presentation varies between the various CTL epitopes as Nef-mediated down-regulation of HLA-A/B is not complete. Own experiments demonstrated that some viral peptides are “resistant” to the negative effects of Nef, as they are still presented to CTL despite low HLA-I expression presumably due to highly efficient processing of the peptides from viral proteins and high binding affinity to the HLA molecules.
In our research project, we are investigating the induction of HIV-1-specific CTL targeting Nef/Vpu-“resistant” CTL epitopes which are still presented to CTL despite the negative effects of Nef and Vpu. For this purpose, we have developed techniques allowing the efficient mapping of Nef/Vpu-“resistant” epitopes. Furthermore, we will analyze whether the recognition of such epitopes correlates to a better suppression of HIV-1 replication and to a better course of HIV-1-infection. The results of this project shall contribute to the development of more efficient HIV-1 vaccines and immunotherapies.
