Verbesserung von DNA-Impfstoffen gegen retrovirale Infektionen durch die funktionelle Blockade von regulatorischen T-Zellen
Final Report Abstract
After more than 30 years of research a HIV vaccine is still not at hand. DNA vectors expressing viral antigens are very safe vaccines, but so far they were not efficient enough to induced broad protective immunity against retroviruses. One strategy to enhance the efficiency of DNA vaccines is to augment effector T cell priming against viral components by manipulating regulatory T cell functions (Treg). Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a molecule that is constitutive expressed on CD4+ Treg cells and antibodies or natural ligands binding this molecule can impair Treg cell suppression. Here we demonstrate using the retroviral Friend Virus (FV) mouse model, that coimmunization of FV antigens along with GITR-Ligand (GITRL) expressed in a bicistronic DNA vector protected mice efficiently against a FV challenge. Coimmunization with the FV-speciflc DNA vaccines and GITRL expressed by separate vectors resulted in the less protective effect and treatment of DNA vaccinated mice with a-GITR antibody did not improve vaccine-induced protection at all. Thus, for an effective priming of immunity against FV, GITRL and viral antigens had to be expressed within the same cell. The data suggest that limitations in DNA vaccination can be overcome by co-expressing co-stimulatory molecules that potentially manipulate the function of Treg cells during priming of anti-retroviral immunity.
