TY - JOUR
T1 - Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV
AU - Hansen, Scott G.
AU - Womack, Jennie L.
AU - Perez, Wilma
AU - Schmidt, Kimberli A.
AU - Marshall, Emily
AU - Iyer, Ravi F.
AU - Rubeor, Hillary Cleveland
AU - Otero, Claire E.
AU - Taher, Husam
AU - Burgt, Nathan H.Vande
AU - Barfield, Richard
AU - Randall, Kurt T.
AU - Morrow, David
AU - Hughes, Colette M.
AU - Selseth, Andrea N.
AU - Gilbride, Roxanne M.
AU - Ford, Julia C.
AU - Caposio, Patrizia
AU - Tarantal, Alice F.
AU - Chan, Cliburn
AU - Malouli, Daniel
AU - Barry, Peter A.
AU - Permar, Sallie R.
AU - Picker, Louis J.
AU - Fruh, Klaus
N1 - Publisher Copyright:
© 2023, Hansen et al.
PY - 2023/3/22
Y1 - 2023/3/22
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.164692
DO - 10.1172/jci.insight.164692
M3 - Article
C2 - 36749635
AN - SCOPUS:85150386071
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - 164692
ER -