Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.
Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs wit...
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Public Library of Science (PLoS)
2021-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009278&type=printable |
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| author | Fredrik Barrenäs Scott G Hansen Lynn Law Connor Driscoll Richard R Green Elise Smith Jean Chang Inah Golez Taryn Urion Xinxia Peng Leanne Whitmore Daniel Newhouse Colette M Hughes David Morrow Kurt T Randall Andrea N Selseth Julia C Ford Roxanne M Gilbride Bryan E Randall Emily Ainslie Kelli Oswald Rebecca Shoemaker Randy Fast William J Bosche Michael K Axthelm Yoshinori Fukazawa George N Pavlakis Barbara K Felber Slim Fourati Rafick-Pierre Sekaly Jeffrey D Lifson Jan Komorowski Ewelina Kosmider Danica Shao Wenjun Song Paul T Edlefsen Louis J Picker Michael Gale |
| author_facet | Fredrik Barrenäs Scott G Hansen Lynn Law Connor Driscoll Richard R Green Elise Smith Jean Chang Inah Golez Taryn Urion Xinxia Peng Leanne Whitmore Daniel Newhouse Colette M Hughes David Morrow Kurt T Randall Andrea N Selseth Julia C Ford Roxanne M Gilbride Bryan E Randall Emily Ainslie Kelli Oswald Rebecca Shoemaker Randy Fast William J Bosche Michael K Axthelm Yoshinori Fukazawa George N Pavlakis Barbara K Felber Slim Fourati Rafick-Pierre Sekaly Jeffrey D Lifson Jan Komorowski Ewelina Kosmider Danica Shao Wenjun Song Paul T Edlefsen Louis J Picker Michael Gale |
| author_sort | Fredrik Barrenäs |
| collection | DOAJ |
| description | Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge. |
| format | Article |
| id | doaj-art-cd57c9263ff449bb8bd672c756c1208a |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-cd57c9263ff449bb8bd672c756c1208a2025-08-20T03:25:19ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-07-01177e100927810.1371/journal.ppat.1009278Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.Fredrik BarrenäsScott G HansenLynn LawConnor DriscollRichard R GreenElise SmithJean ChangInah GolezTaryn UrionXinxia PengLeanne WhitmoreDaniel NewhouseColette M HughesDavid MorrowKurt T RandallAndrea N SelsethJulia C FordRoxanne M GilbrideBryan E RandallEmily AinslieKelli OswaldRebecca ShoemakerRandy FastWilliam J BoscheMichael K AxthelmYoshinori FukazawaGeorge N PavlakisBarbara K FelberSlim FouratiRafick-Pierre SekalyJeffrey D LifsonJan KomorowskiEwelina KosmiderDanica ShaoWenjun SongPaul T EdlefsenLouis J PickerMichael GaleSimian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009278&type=printable |
| spellingShingle | Fredrik Barrenäs Scott G Hansen Lynn Law Connor Driscoll Richard R Green Elise Smith Jean Chang Inah Golez Taryn Urion Xinxia Peng Leanne Whitmore Daniel Newhouse Colette M Hughes David Morrow Kurt T Randall Andrea N Selseth Julia C Ford Roxanne M Gilbride Bryan E Randall Emily Ainslie Kelli Oswald Rebecca Shoemaker Randy Fast William J Bosche Michael K Axthelm Yoshinori Fukazawa George N Pavlakis Barbara K Felber Slim Fourati Rafick-Pierre Sekaly Jeffrey D Lifson Jan Komorowski Ewelina Kosmider Danica Shao Wenjun Song Paul T Edlefsen Louis J Picker Michael Gale Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. PLoS Pathogens |
| title | Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. |
| title_full | Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. |
| title_fullStr | Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. |
| title_full_unstemmed | Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. |
| title_short | Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy. |
| title_sort | interleukin 15 response signature predicts rhcmv siv vaccine efficacy |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009278&type=printable |
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