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...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.164692 |
| _version_ | 1827767936165609472 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Scott G. Hansen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:06:24Z |
| format | Article |
| id | doaj.art-2cef4c4bc58642d4a61f2fb76b14a405 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:24Z |
| publishDate | 2023-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-2cef4c4bc58642d4a61f2fb76b14a4052023-11-07T16:25:22ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-03-0186Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIVScott G. HansenJennie L. WomackWilma PerezKimberli A. SchmidtEmily MarshallRavi F. IyerHillary Cleveland RubeorClaire E. OteroHusam TaherNathan H. Vande BurgtRichard BarfieldKurt T. RandallDavid MorrowColette M. HughesAndrea N. SelsethRoxanne M. GilbrideJulia C. FordPatrizia CaposioAlice F. TarantalCliburn ChanDaniel MalouliPeter A. BarrySallie R. PermarLouis J. PickerKlaus FrühRhesus 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.https://doi.org/10.1172/jci.insight.164692AIDS/HIVVirology |
| spellingShingle | 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 Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV JCI Insight AIDS/HIV Virology |
| title | Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV |
| title_full | Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV |
| title_fullStr | Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV |
| title_full_unstemmed | Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV |
| title_short | Late gene expression–deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV |
| title_sort | late gene expression deficient cytomegalovirus vectors elicit conventional t cells that do not protect against siv |
| topic | AIDS/HIV Virology |
| url | https://doi.org/10.1172/jci.insight.164692 |
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