TY - JOUR
T1 - The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination
AU - Tomalka, Jeffrey Alan
AU - Pelletier, Adam Nicolas
AU - Fourati, Slim
AU - Latif, Muhammad Bilal
AU - Sharma, Ashish
AU - Furr, Kathryn
AU - Carlson, Kevin
AU - Lifton, Michelle
AU - Gonzalez, Ana
AU - Wilkinson, Peter
AU - Franchini, Genoveffa
AU - Parks, Robert
AU - Letvin, Norman
AU - Yates, Nicole
AU - Seaton, Kelly
AU - Tomaras, Georgia
AU - Tartaglia, Jim
AU - Robb, Merlin L.
AU - Michael, Nelson L.
AU - Koup, Richard
AU - Haynes, Barton
AU - Santra, Sampa
AU - Sekaly, Rafick Pierre
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85115425599
U2 - 10.1038/s41590-021-01026-9
DO - 10.1038/s41590-021-01026-9
M3 - Article
C2 - 34556879
AN - SCOPUS:85115425599
SN - 1529-2908
VL - 22
SP - 1294
EP - 1305
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -