Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: PLoS Pathogens, Vol 17, Iss 7, p e1009278 (2021)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1009278
Popis: 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.
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