Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.
Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.
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DOI：
10.1371/journal.ppat.1009278
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Gale M Jr
中科院分区：
文献类型：
--
作者：
Barrenäs F;Hansen SG;Law L;Driscoll C;Green RR;Smith E;Chang J;Golez I;Urion T;Peng X;Whitmore L;Newhouse D;Hughes CM;Morrow D;Randall KT;Selseth AN;Ford JC;Gilbride RM;Randall BE;Ainslie E;Oswald K;Shoemaker R;Fast R;Bosche WJ;Axthelm MK;Fukazawa Y;Pavlakis GN;Felber BK;Fourati S;Sekaly RP;Lifson JD;Komorowski J;Kosmider E;Shao D;Song W;Edlefsen PT;Picker LJ;Gale M Jr
用表达猴免疫缺陷病毒（SIV）蛋白的68-1株恒河猴巨细胞病毒（RhCMV）载体（RhCMV/SIV）接种的恒河猴（RM）的猴免疫缺陷病毒（SIV）攻毒导致二元结果：在约55%的接种RM中严格控制并随后清除高致病性SIV，其余45%无保护作用。尽管先前的工作表明，非常规限制性的、SIV特异性的、效应记忆（EM）偏向的CD 8 + T细胞应答是有效性所必需的，但这些应答的幅度并不能预测有效性，并且尚未阐明68-1 RhCMV/SIV载体接种的RM中保护与非保护的基础。在这里，我们报告了68-1 RhCMV/SIV载体给药显著改变了接种疫苗的RM的全血转录组，持续诱导特异性免疫相关途径，包括免疫细胞、toll样受体（TLR）、炎性小体/细胞死亡和白细胞介素-15（IL-15）信号传导，与随后的疫苗效力显著相关。用IL-15治疗单独的RM队列证实了这种细胞因子在保护特征中的中心参与，连接了与RhCMV/SIV疫苗功效相关的主要先天性和适应性免疫基因表达网络。在接种疫苗和攻毒RM的独立验证队列中，也证明IL-15应答特征较基线的变化与疫苗效力显著相关。对疫苗接种的差异IL-15基因集应答与该途径的疫苗接种前活性密切相关，IL-15应答基因的基线表达降低与疫苗诱导的IL-15信号传导诱导和后续疫苗保护作用显著相关，表明需要稳健的从头疫苗诱导的IL-15信号传导应答来编程疫苗功效。因此，RhCMV/SIV疫苗赋予以IL-15为特征的先天性和适应性免疫途径的协调和持续诱导，IL-15是CD 8 + T细胞功能的已知调节剂，其支持疫苗引发的非常规限制性CD 8 + T细胞介导针对SIV攻击的保护的能力。基于菌株68-1 RhCMV的SIV插入片段表达疫苗载体在略超过一半的接种猴中引发稳健的、高度效应记忆偏倚的、非常规限制性T细胞应答，其与攻击后前所未有的SIV控制水平（复制停滞导致清除）相关。由于用有效的68-1疫苗接种的猴的有效性不能通过免疫原性的标准测量来预测，因此我们使用已知攻击结果的RhCMV/SIV疫苗接种的猴的功能基因组学分析来鉴定保护的免疫相关性。我们发现疫苗功效与疫苗诱导的对IL-15的应答显著相关，所述应答包括免疫细胞、炎症、TLR信号传导和细胞死亡编程应答途径的调节。这些数据表明，RhCMV/SIV的疗效是由疫苗介导的先天性和适应性免疫途径的协调和持续诱导引起的，其特征在于IL-15，一种已知的CD 8+效应记忆T细胞功能调节剂，与疫苗诱导的CD 8 + T细胞合作介导疗效。
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. SIV insert-expressing vaccine vectors based on strain 68–1 RhCMV elicit robust, highly effector-memory-biased, unconventionally restricted T cell responses that are associated with an unprecedented level of SIV control after challenge (replication arrest leading to clearance) in slightly over half of vaccinated monkeys. Since efficacy among monkeys vaccinated with the effective 68–1 vaccine is not predicted by standard measures of immunogenicity, we used functional genomics analysis of RhCMV/SIV vaccinated monkeys with known challenge outcomes to identify immune correlates of protection. We found that vaccine efficacy significantly correlates with a vaccine-induced response to IL-15 that includes modulation of immune cell, inflammation, TLR signaling, and cell death programming response pathways. These data suggest that RhCMV/SIV efficacy results from a coordinated and sustained vaccine-mediated induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ effector-memory T cell function, that cooperates with vaccine-elicited CD8+ T cells to mediate efficacy.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1126/science.aac9475
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hansen SG;Wu HL;Burwitz BJ;Hughes CM;Hammond KB;Ventura AB;Reed JS;Gilbride RM;Ainslie E;Morrow DW;Ford JC;Selseth AN;Pathak R;Malouli D;Legasse AW;Axthelm MK;Nelson JA;Gillespie GM;Walters LC;Brackenridge S;Sharpe HR;López CA;Früh K;Korber BT;McMichael AJ;Gnanakaran S;Sacha JB;Picker LJ
通讯作者：
Picker LJ
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Hansen, Scott G.;Womack, Jennie;Fruh, Klaus
通讯作者：
Fruh, Klaus
影响因子：
64.8
作者：
Hansen, Scott G.;Ford, Julia C.;Lewis, Matthew S.;Ventura, Abigail B.;Hughes, Colette M.;Coyne-Johnson, Lia;Whizin, Nathan;Oswald, Kelli;Shoemaker, Rebecca;Swanson, Tonya;Legasse, Alfred W.;Chiuchiolo, Maria J.;Parks, Christopher L.;Axthelm, Michael K.;Nelson, Jay A.;Jarvis, Michael A.;Piatak, Michael, Jr.;Lifson, Jeffrey D.;Picker, Louis J.
通讯作者：
Picker, Louis J.