美国凯斯西储大学Rafick Pierre Sekaly和美国哈佛医学院Sampa Santra研究组合作取得最新进展。他们发现转录因子CREB1 是免疫原性和降低ALVAC 疫苗接种后人类免疫缺陷病毒 1 (HIV-1)获得的机制驱动因子。2021年9月23日在国际知名学术期刊《自然—免疫学》发表了这一成果。

他们展示了重组金丝雀痘载体 ALVAC + Alum 对转录因子 CREB1 及其靶基因的诱导增强了非人类灵长类动物 (NHP) 的免疫原性，并预测了 RV144 试验中 HIV-1 感染的减少。这些靶基因包括那些编码细胞因子/趋化因子的基因，这些细胞因子/趋化因子与 NHP 中针对猿猴免疫缺陷病毒攻击的增强保护相关。CREB1 靶基因的表达可能来自直接 cGAMP（STING 激动剂）调节的 p-CREB1 活性，该活性驱动 CD4+ T 细胞和 B 细胞募集到抗原呈递部位。

重要的是，与用 ALVAC + Alum 免疫的 NHP 不同，用 ALVAC + MF59 免疫的那些，HVTN702 试验中没有显示出对 HIV 感染的保护的方案，表现出显著降低的 CREB1 靶基因表达。他们的综合系统生物学方法已验证 CREB1 作为疫苗作用的关键驱动因素，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。

据了解，开发有效的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。

附：英文原文

Title: The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination

Author: Tomalka, Jeffrey Alan, Pelletier, Adam Nicolas, Fourati, Slim, Latif, Muhammad Bilal, Sharma, Ashish, Furr, Kathryn, Carlson, Kevin, Lifton, Michelle, Gonzalez, Ana, Wilkinson, Peter, Franchini, Genoveffa, Parks, Robert, Letvin, Norman, Yates, Nicole, Seaton, Kelly, Tomaras, Georgia, Tartaglia, Jim, Robb, Merlin L., Michael, Nelson L., Koup, Richard, Haynes, Barton, Santra, Sampa, Sekaly, Rafick Pierre

Issue&Volume: 2021-09-23

Abstract: 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.

DOI: 10.1038/s41590-021-01026-9

Source: https://www.nature.com/articles/s41590-021-01026-9