OVERALL - PROJECT SUMMARY
Almost 2 decades ago our research group began development of vaccine vectors based on the persistent ß-
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.