Cytomegaloviral determinants of CD8 + T cell programming and RhCMV/SIV vaccine efficacy

• Published in: Science immunology 2021-03, Vol.6 (57)
• Main Authors: Malouli, Daniel, Hansen, Scott G, Hancock, Meaghan H, Hughes, Colette M, Ford, Julia C, Gilbride, Roxanne M, Ventura, Abigail B, Morrow, David, Randall, Kurt T, Taher, Husam, Uebelhoer, Luke S, McArdle, Matthew R, Papen, Courtney R, Espinosa Trethewy, Renee, Oswald, Kelli, Shoemaker, Rebecca, Berkemeier, Brian, Bosche, William J, Hull, Michael, Greene, Justin M, Axthelm, Michael K, Shao, Jason, Edlefsen, Paul T, Grey, Finn, Nelson, Jay A, Lifson, Jeffrey D, Streblow, Daniel, Sacha, Jonah B, Früh, Klaus, Picker, Louis J
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Viral - genetics; Antigens, Viral - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cellular Reprogramming - genetics; Cellular Reprogramming - immunology; Cytomegalovirus - immunology; Cytomegalovirus Infections - veterinary; Genetic Engineering - methods; Genetic Vectors - genetics; Immunogenicity, Vaccine; Immunologic Memory; Macaca mulatta; Monkey Diseases - immunology; Monkey Diseases - prevention & control; Monkey Diseases - virology; Open Reading Frames - genetics; Open Reading Frames - immunology; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian Immunodeficiency Virus - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Vaccine Efficacy; Viral Vaccines - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.abg5413

Simian immunodeficiency virus (SIV) insert-expressing, 68-1 rhesus cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8 T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) have not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions ( and ), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences ( ; ) leads to either of two distinct CD8 T cell response types-MHC-Ia-restricted only or a mix of MHC-II- and MHC-Ia-restricted CD8 T cells. Response magnitude and functional differentiation are similar to RhCMV 68-1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8 T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector.