Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV

Rhesus cytomegalovirus-based (RhCMV-based) vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory-based (EM-biased) CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex-E (MHC-E) instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the antihost intrinsic immunity factor phosphoprotein 71 (pp71). Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506 analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RMs at doses of ≥ 1 × 106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.

 

Comments：

The passage describes a study in which researchers examined the efficacy of a more stringent attenuation strategy on the RhCMV/SIV vaccine vector, which induces immune responses that protect against SIV in rhesus macaques. The new strategy involved fusing the FK506-binding protein degradation domain to Rh108, an essential gene transcription factor in HCMV. This fusion created RhCMV/SIV vectors that only replicate in the presence of the FK506 analog Shield-1.

The study found that the Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive rhesus macaques, but these responses only targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. This suggests that Rh108-dependent late gene expression is required for both the induction of MHC-E-restricted T cells and protection against SIV.

Related Products

Cat.No.	Product Name	Information
S3469	Shield-1	Shield-1 is a specific, cell-permeant and high-affinity ligand of FK506-binding protein-12 (FKBP). Shield-1 reverses the instability by binding to mutated FKBP (mtFKBP), allowing conditional expression of mtFKBP-fused proteins. Shield-1 stabilizes the entire fusion protein.

Related Targets

FKBP