Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV
Scott G. Hansen, … , Louis J. Picker, Klaus Früh
Scott G. Hansen, … , Louis J. Picker, Klaus Früh
Published February 7, 2023
Citation Information: JCI Insight. 2023;8(6):e164692. https://doi.org/10.1172/jci.insight.164692.
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Research Article AIDS/HIV Virology

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

Abstract

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.

Authors

Scott G. Hansen, Jennie L. Womack, Wilma Perez, Kimberli A. Schmidt, Emily Marshall, Ravi F. Iyer, Hillary Cleveland Rubeor, Claire E. Otero, Husam Taher, Nathan H. Vande Burgt, Richard Barfield, Kurt T. Randall, David Morrow, Colette M. Hughes, Andrea N. Selseth, Roxanne M. Gilbride, Julia C. Ford, Patrizia Caposio, Alice F. Tarantal, Cliburn Chan, Daniel Malouli, Peter A. Barry, Sallie R. Permar, Louis J. Picker, Klaus Früh

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Figure 6

Rh108-deficient RhCMV/SIV vectors do not protect against SIV challenge.

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Rh108-deficient RhCMV/SIV vectors do not protect against SIV challenge. ...
Fifteen RhCMV seropositive RMs were s.c. vaccinated at weeks 0 and 18 with a 3-vector set of 68-1 RhCMV/FKBP-Rh108 vectors individually expressing SIV Gag, Rev/Tat/Nef, and Pol (each vector given at 5 × 106 PFU). After first vaccination, RMs were followed for 78 weeks prior to initiation of repeated, limiting dose SIVmac239 challenge. Previously published cohorts of 15 RMs vaccinated twice (weeks 0 and 18 with the 68-1 RhCMV/SIV 3-vector set; SIV Gag, Rev/Tat/Nef and 5′-Pol; 5 × 106 PFU per vector) or left unvaccinated were used as positive and negative controls, respectively (16). (A) Comparison of the prechallenge SIV-specific CD4+ and CD8+ T cell response magnitude of the FKBP-Rh108 RhCMV/SIV vector–vaccinated RMs (week 78) to plateau phase responses of the Rh108-intact 68-1 RhCMV/SIV–vaccinated RMs (mean from week 61 to 80). Box plots show jittered points and a box from first to third quartiles and a line at the median, with whiskers extending to the farthest data point within 1.5× interquartile range above and below the box. Statistical significance between the 2 groups was determined by Wilcoxon Rank-Sum test with multiple testing correction via FDR. (B) Outcome of SIVmac239 challenge after establishment of infection with repeated limited dose challenge. As previously described (16), SIV infection was documented in the protected RMs in the Rh108-intact 68-1 RhCMV vector vaccinated group by the de novo development of SIV Vif–specific T cell responses, detection of SIV infection in tissues by PCR, and adoptive transfer of leukocytes to naive RMs. Statistical significance between the 68-1 RhCMV/SIV cohort and the 68-1 RhCMV/FKBP-Rh108/SIV cohort was determined by Fisher’s exact test.