In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-6), p. e1009278-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009278
DOI:
10.1371/journal.ppat.1009278.g001
DOI:
10.1371/journal.ppat.1009278.g002
DOI:
10.1371/journal.ppat.1009278.g003
DOI:
10.1371/journal.ppat.1009278.g004
DOI:
10.1371/journal.ppat.1009278.g005
DOI:
10.1371/journal.ppat.1009278.g006
DOI:
10.1371/journal.ppat.1009278.s001
DOI:
10.1371/journal.ppat.1009278.s002
DOI:
10.1371/journal.ppat.1009278.s003
DOI:
10.1371/journal.ppat.1009278.s004
DOI:
10.1371/journal.ppat.1009278.s005
DOI:
10.1371/journal.ppat.1009278.s006
DOI:
10.1371/journal.ppat.1009278.s007
DOI:
10.1371/journal.ppat.1009278.s008
DOI:
10.1371/journal.ppat.1009278.s009
DOI:
10.1371/journal.ppat.1009278.s010
DOI:
10.1371/journal.ppat.1009278.s011
DOI:
10.1371/journal.ppat.1009278.r001
DOI:
10.1371/journal.ppat.1009278.r002
DOI:
10.1371/journal.ppat.1009278.r003
DOI:
10.1371/journal.ppat.1009278.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1