RhCMV/SIV tropism modulation programs unconventional CD8+ T cell priming and vaccine efficacy

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.64-64.18
• Main Authors: Hancock, Meaghan, Hansen, Scott, Malouli, Daniel, Marshall, Emily, Hughes, Collette, Randall, Kurt T., Morrow, David, Ford, Julia, Gilbride, Roxanne, Selseth, Andrea, Trethewy, Renee Espinosa, Bishop, Lindsey, Oswald, Kelli, Shoemaker, Rebecca, Berkemeier, Brian, Bosche, William, Hull, Michael, Nekorchuk, Michael, Busman-Sahay, Kathleen, Estes, Jacob, Axthelm, Michael, Smedley, Jeremy, Shao, Danica, Edlefsen, Paul, Lifson, Jeffrey, Fruh, Klaus, Nelson, Jay, Picker, Louis J
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.64.18

Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens demonstrate a vaccine efficacy where 50–60% of vaccinated rhesus macaques are protected from SIV challenge. Intriguingly, RhCMV/SIV vectors elicit CD8+ T cells recognizing epitopes presented by MHC-II and MHC-E instead of MHC-Ia. We are studying how these unconventional T cell responses are elicited and contribute to the efficacy against SIV challenge. Here we utilize host microRNA (miRNA)-mediated vector tropism restriction to show that MHC-II- and MHC-E-restricted responses are primed by directly infected, non-overlapping cell types in rhesus macaques. Targeting essential RhCMV genes with myeloid cell-selective miR-142-3p eliminated MHC-E-restricted CD8+ T cell priming, yielding an exclusively MHC-II-restricted response, whereas endothelial cell-selective miR-126-3p targeting eliminated MHC-II-restricted CD8+ T cell priming, yielding an exclusively MHC-E-restricted response. Incorporation of both restriction elements reverts CD8+ T cell responses back to conventional MHC-Ia restriction. Using these otherwise isogenic vectors we show that although they demonstrate similar overall immunogenicity, only the vectors programmed to elicit MHC-E-restricted CD8+ T cell responses provided protection against SIV challenge. The MHC-E-only RhCMV/SIV vaccine efficacy did not exceed that of the parental 68-1 RhCMV/SIV vectors (that elicits both MHC-II and MHC-E responses) indicating that while the MHC-II-restricted CD8+ T cell responses are neutral to overall vaccine efficacy, an additional component of 68-1 RhCMV/SIV-induced immunity contributes to overall vaccine efficacy. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI124377 and U19 AI128741 to LJP; the Oregon National Primate Research Center Core grant from the National Institutes of Health, Office of the Director (P51 OD011092); contracts from the National Cancer Institute (# HHSN261200800001E) to JDL; and the Bill and Melinda Gates Foundation grant OPP1107409.