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

Publication ,  Journal Article
Hansen, SG; Womack, JL; Perez, W; Schmidt, KA; Marshall, E; Iyer, RF; Cleveland Rubeor, H; Otero, CE; Taher, H; Vande Burgt, NH; Barfield, R ...
Published in: JCI Insight
March 22, 2023

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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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 22, 2023

Volume

8

Issue

6

Location

United States

Related Subject Headings

  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Macaca mulatta
  • Humans
  • Gene Expression
  • Cytomegalovirus
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

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Hansen, S. G., Womack, J. L., Perez, W., Schmidt, K. A., Marshall, E., Iyer, R. F., … Früh, K. (2023). Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV. JCI Insight, 8(6). https://doi.org/10.1172/jci.insight.164692
Hansen, Scott G., Jennie L. Womack, Wilma Perez, Kimberli A. Schmidt, Emily Marshall, Ravi F. Iyer, Hillary Cleveland Rubeor, et al. “Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV.JCI Insight 8, no. 6 (March 22, 2023). https://doi.org/10.1172/jci.insight.164692.
Hansen SG, Womack JL, Perez W, Schmidt KA, Marshall E, Iyer RF, et al. Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV. JCI Insight. 2023 Mar 22;8(6).
Hansen, Scott G., et al. “Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV.JCI Insight, vol. 8, no. 6, Mar. 2023. Pubmed, doi:10.1172/jci.insight.164692.
Hansen SG, Womack JL, Perez W, Schmidt KA, Marshall E, Iyer RF, Cleveland Rubeor H, Otero CE, Taher H, Vande Burgt NH, Barfield R, Randall KT, Morrow D, Hughes CM, Selseth AN, Gilbride RM, Ford JC, Caposio P, Tarantal AF, Chan C, Malouli D, Barry PA, Permar SR, Picker LJ, Früh K. Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV. JCI Insight. 2023 Mar 22;8(6).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

March 22, 2023

Volume

8

Issue

6

Location

United States

Related Subject Headings

  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Macaca mulatta
  • Humans
  • Gene Expression
  • Cytomegalovirus
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences