Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy

Abstract

Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex (MHC)-II and MHC-E, not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors, but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.

Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy

“…In conclusion, these studies provide important new insight into the unique "all or none" viral replication arrest efficacy of 68-1 RhCMV/SIV vectored vaccines, indicating that not only is this efficacy associated with elicitation of SIV-specific MHC-E-restricted CD8 + T cells, as previously described [13,14], in the setting of such responses, it is also strongly correlated with a specific, vaccine-induced innate and adaptive immune signaling signature. Understanding the biologic interaction of these two strong efficacy correlates will likely allow for refining and improving the predictive signature, but more importantly, will almost certainly reveal the fundamental biologic mechanisms underlying SIV replication arrest, which could have farreaching implications for both vaccine and non-vaccine approaches to control of SIV/HIV infection.…”

“…over half of vaccinees (protection), whereas the remaining vaccinees manifest primary infection SIV dynamics similar to unvaccinated controls (non-protection). Previous work associated the early effective intercept of nascent SIV with the characteristic effector-memory-biased T cell response elicited by RhCMV [5][6][7][8] and more recent work has strongly linked efficacy with the also unprecedented MHC-E-restricted CD8 + T cell response that results from the unique strain 68-1 RhCMV genotype [12][13][14]. However, the very consistent, binary 50-60% efficacy across multiple studies has not been explained, as no standard immunologic parameter has been consistently correlated with protection after challenge, including both this study and prior studies [6][7][8].…”

“…These gene modifications had the remarkable effect of programming both the virus-and SIV insert-specific CD8 + T cells induced by this vector to recognize epitopes restricted by either MHC-E or MHC-II, but not classical MHC-Ia [11][12][13]. Differential repair of these genes reverts epitope restriction of vector-elicited CD8 + T cells to MHC-Ia or MHC-Ia mixed with MHC-II, whereas another mutation of 68-1 RhCMV (deletion of Rh67) results in exclusively MHC-II-restricted CD8 + T cells [13,14]. Although the MHC-Ia-and/or MHC-II-restricted CD8 + T cell responses elicited by these other RhCMV/SIV vectors manifest similar phenotypic and functional characteristics, only the original 68-1 vector shows efficacy against SIV [13,14], strongly implicating the MHC-E-restricted, SIV-specific CD8 + T cells as the active adaptive component of this nonantibody-inducing vaccine.…”

“…Differential repair of these genes reverts epitope restriction of vector-elicited CD8 + T cells to MHC-Ia or MHC-Ia mixed with MHC-II, whereas another mutation of 68-1 RhCMV (deletion of Rh67) results in exclusively MHC-II-restricted CD8 + T cells [13,14]. Although the MHC-Ia-and/or MHC-II-restricted CD8 + T cell responses elicited by these other RhCMV/SIV vectors manifest similar phenotypic and functional characteristics, only the original 68-1 vector shows efficacy against SIV [13,14], strongly implicating the MHC-E-restricted, SIV-specific CD8 + T cells as the active adaptive component of this nonantibody-inducing vaccine. However, to date, no quantitative parameter of the 68-1 RhCMV/ SIV-induced T cell responses has consistently correlated with the binary outcome (protection vs. non-protection) after SIV challenge [6][7][8].…”

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

“…h) HLA-E restricted KL9 and KF11 specific responses can be generated by in-vitro priming of CD8 T cells obtained from HIV seronegative donors. Finally, as HLA-E restricted CD8 T cells may have important implications for HIV-1 vaccines (30,(43)(44)(45), we next determined whether such responses can be primed in HIV seronegative donors as shown in a recent study (44). We generated HLA-E restricted KF11 specific CD8 T-cell lines by in-vitro priming using PBMCs obtained from three HIV seronegative healthy donors.…”