Abstract
Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells that recognize peptide epitopes presented by major histocompatibility complex (MHC)-II and MHC-E molecules, instead of MHC-Ia, and are uniquely able to mediate stringent control and subsequent clearance of highly pathogenic SIV in ∼50% of vaccinated rhesus macaques (RMs). We show that the MHC-E ligand VMAPRTLLL (VL9), encoded by the Rh67 gene (or its HCMV UL40 counterpart) is required for recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells via its ability to promote intracellular MHC-E transport. Moreover, deletion of Rh67 from 68-1 RhCMV/SIV vectors, or mutation of its embedded VL9 ligand, abrogated induction of MHC-E-restricted CD8+ T cell responses, leaving responses that exclusively target MHC-II-restricted epitopes. These MHC-II-presented CD8+ T cell responses, though comparable in response magnitude and functional differentiation to responses arising from the efficacious 68-1 vector, did not protect RMs against SIV challenge, indicating that Rh67/UL40-enabled direct priming of MHC-E-targeted CD8+ T cells is a crucial element of RhCMV/SIV vaccine efficacy.
One Sentence Summary A cytomegalovirus protein (Rh67/UL40) that upregulates MHC-E expression on RhCMV/SIV-vector infected cells is required for induction of MHC-E-restricted CD8+ T cells and for protection against SIV.
Competing Interest Statement
OHSU, SGH, LJP, and KF have a substantial financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. SGH, LJP, and KF are also consultants to Vir Biotechnology, Inc., and JBS has received compensation for consulting for Vir Biotechnology, Inc. SGH, LJP, and KF are co-inventors of patent WO 2011 143650 A2 Recombinant RhCMV and HCMV vectors and uses thereof licensed to Vir Biotechnology, Inc. SGH, LJP, KF, and DM are co-inventors of patent US2016 0010112 A1 Cytomegalovirus vectors enabling control of T cell targeting licensed to Vir Biotechnology, Inc. SGH, LJP and KF are co-inventors of patent US2017/0143809 A1 CMV vectors comprising microRNA recognition elements licensed to Vir Biotechnology, Inc. These potential individual and institutional conflicts of interest have been reviewed and managed by OHSU.
