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The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination
Nature Immunology ( IF 27.7 ) Pub Date : 2021-09-23 , DOI: 10.1038/s41590-021-01026-9
Jeffrey Alan Tomalka 1, 2 , Adam Nicolas Pelletier 1 , Slim Fourati 1, 2 , Muhammad Bilal Latif 1, 2 , Ashish Sharma 2 , Kathryn Furr 3 , Kevin Carlson 3 , Michelle Lifton 3 , Ana Gonzalez 3 , Peter Wilkinson 1 , Genoveffa Franchini 4 , Robert Parks 5 , Norman Letvin 3 , Nicole Yates 5 , Kelly Seaton 5 , Georgia Tomaras 5 , Jim Tartaglia 6 , Merlin L Robb 7 , Nelson L Michael 7 , Richard Koup 8 , Barton Haynes 5 , Sampa Santra 3 , Rafick Pierre Sekaly 1, 2
Affiliation  

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.



中文翻译:


转录因子 CREB1 是免疫原性的机制驱动因素,并且在 ALVAC 疫苗接种后减少 HIV-1 获得



开发有效的人类免疫缺陷病毒 1 (HIV-1) 疫苗需要先天免疫细胞和适应性免疫细胞之间的协同作用。在这里,我们表明,重组金丝雀痘载体 ALVAC + Alum 对转录因子 CREB1 及其靶基因的诱导增强了非人灵长类动物 (NHP) 的免疫原性,并预测 RV144 试验中 HIV-1 获得性减少。这些靶基因包括那些编码与 NHP 中针对猿猴免疫缺陷病毒攻击的增强保护相关的细胞因子/趋化因子的基因。 CREB1 靶基因的表达可能是由 cGAMP(STING 激动剂)直接调节的 p-CREB1 活性引起的,该活性驱动 CD4 + T 细胞和 B 细胞募集到抗原呈递位点。重要的是,与用 ALVAC + Alum 免疫的 NHP 不同,用 ALVAC + MF59 免疫的 NHP(HVTN702 试验中的方案没有显示出对 HIV 感染的保护作用)表现出 CREB1 靶基因表达显着降低。我们的综合系统生物学方法已验证 CREB1 是疫苗功效的关键驱动因素,并强调触发 CREB1 信号传导的佐剂可能对有效的 HIV-1 疫苗至关重要。

更新日期:2021-09-23
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