Immunologic and Virologic Basis of RhCMV/SIV Vaccine-Induced Replication Arrest Efficacy

OVERALL - PROJECT SUMMARY Almost 2 decades ago our research group began development of vaccine vectors based on the persistent β- herpesvirus Cytomegalovirus (CMV) because of the ability of CMV to elicit and indefinitely maintain high frequency, effector-differentiated T cell responses in diverse tissues. Using the rhesus macaque (RM) model,

we have demonstrated that not only do RhCMV/SIV vaccines provide superior efficacy against highly pathogenic SIV challenge than conventional SIV vaccines (in aggregate, 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection), this efficacy is of an entirely new pattern – early SIV replication arrest followed by

eventual viral clearance – and is mediated by a novel immune response – MHC-E-restricted, effector memory- differentiated CD8+ T cells (which to date can only be elicited by CMV vectors with specific genetic programming). We also know that the efficacy of MHC-E targeted CD8+ T cell responses is predicted by a whole blood

transcriptomic signature featuring IL-15 signaling, but the mechanisms responsible for complete arrest and subsequent clearance of nascent SIV infection are not defined, including the questions of why MHC-E-restricted epitope recognition is required for efficacy, how these cells mediate replication arrest, and how the protective

whole blood transcriptomic signature influences these unique effector responses. In this program, we seek to both answer these questions and develop detailed criteria for “replication arrest” efficacy for guiding ongoing phase I/II clinical testing of human CMV/HIV vaccines. The proposed program will include the following 3

projects: 1) Immunologic and virologic characterization of RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy, 2) Characterization of the in vivo T cell (and overall immune) interception of primary SIV infection after vaccination with differentially response programmed RhCMV/SIV vectors (MHC-E- vs. MHC-II- vs. MHC-Ia-

restricted) and a conventional prime-boost SIV vaccine (MHC-Ia-restricted), and 3) Determination of the minimal MHC-E-restricted SIV epitope targeting required for RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy. These projects will be supported by 4 cores: A) Administration, B) NHP, C) Advanced Spatial Analysis,

and D) `Omics, Bioinformatics, and Data Management. In addition to guiding current and future clinical testing of HMCV/HIV vaccines, the understanding the immunologic basis of “SIV replication arrest” efficacy and the role of MHC-E-restricted CD8+ T cells in this process will have broad implications for HIV cure approaches, as well as

inform the use of MHC-E-restricted CD8+ T cells as universal (MHC haplotype independent) effectors for immunotherapies directed at other infectious diseases or cancer.