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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)1294-1305
Number of pages12
JournalNature Immunology
Volume22
Issue number10
DOIs
StatePublished - Oct 2021
Externally publishedYes

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