About us
Vectors based on cytomegalovirus (CMV) represent a novel vaccine platform that maintains high frequencies of non-exhausted effector memory T cells in both CMV sero-positive and sero-negative hosts. In non-human primate models, CMV-vectored vaccines provide unprecedented protection against simian immunodeficiency virus (SIV). Uniquely, CMV vectors can be genetically altered to elicit highly diverse CD8+ T cell responses that recognize peptides presented by MHC class II or non-polymorphic MHC-E rather than conventional MHC-I. We have identified the viral determinants that control such unconventional T cell priming and demonstrated that MHC-E-restricted CD8+ T cells are required for protection against SIV. Based on this research we designed a novel type of HIV vaccine that is currently in clinical testing.
Figure legend: The figure shows an overview of the different types of CD8-positive T cells that can be elicited in response to recombinant rhesus cytomegalovirus (RhCMV). Depending on the genetic modifications introduced into RhCMV we can elicit CD8+ T cells that recognize small peptides (=epitopes) either in the context of major histocompatibility class Ia, class E or class II. T cells are thus “restricted” by either MHC-I, MHC-E or MHC-II. Unmodified (wildtype) RhCMV elicits T cells that recognize “conventional” epitopes that presented by MHC-Ia. However, upon deletion of the US11 gene, RhCMV additionally elicits T cells to “canonical” epitopes that are immunodominant in the context of other vaccines. Deletion of a series of the viral chemokine-like genes (UL128, UL130, UL146 and UL147) dramatically changes the epitope recognition. Instead of MHC-Ia, all CD8+ T cells are now MHC-II or MHC-E restricted. By additionally deleting UL40 or US28, all elicited T cells (CD8+ and CD4+) are MHC-II restricted. This is also observed when targeting sites for the myeloid-cell specific micro RNA miR142 is inserted into essential RhCMV genes. In contrast, insertion of endothelial cell specific miR126 results in RhCMV that elicits exclusively MHC-E-restricted CD8+ T cells.
