This IPCAVD program proposal builds on an innovative strategy for AIDS vaccine development that takes advantage of the ability of recombinant strain 68-1 rhesus CMV (RhCMV) vectors expressing SIV antigens to elicit long-lived, tissue-based effector memory CD8+ T cell responses that are specifically restricted by MHC-II and MHC-E, rather than by classical MHC-Ia. We have demonstrated in rhesus macaques (RM) that these unique immune responses result in, and are required for, stringent control and eventual clearance of highly pathogenic SIV in 54% of vaccinated RM that were mucosally challenged with the highly pathogenic SIVmac239 clone. Recently, we have also shown that the deletion of Rh157.5/Rh157.4 genes in RhCMV (the RhCMV homologs of the HCMV UL128 and UL130 genes) is necessary for the induction of unconventional CD8+ T cell restriction and thereby, the efficacy of our vaccine. We have also begun to discover other RhCMV gene loci and viral tropism determinants participate in the programming of various aspects of the CD8+ T cell immune response, for the first time allowing for the creation of ?response-programmed? vaccine vectors. This IPCAVD program seeks to further determine the mechanisms of CD8+ T cell unconventional response programming by RhCMV, and to define the nature the responses required for protection against SIV challenge. This knowledge will be then used to design and manufacture next-generation human CMV (HCMV) vectors for safety and immunogenicity testing in HIV/AIDS vaccine clinical trials. To accomplish all of this, this proposal brings together experienced investigators that provide complementary expertise in their projects with the common goals of designing, constructing, and testing the immunogenicity, efficacy, and safety of such response-programmed vaccine vectors. Core C will play a key role in supporting these efforts and integrating the different projects by the provision of standardized virology services and assays. Specifically, Core C will support the project-specific in vivo studies through production and characterization of recombinant RhCMV and HCMV vectors, monitoring of virus loads and secretions, and ultrasensitive PCR characterization of virus biodistribution in host tissues.
|Walters, Lucy C; Harlos, Karl; Brackenridge, Simon et al. (2018) Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat Commun 9:3137|