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.
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Data availability
No restrictions will be placed on data or material sharing used to generate Figs. 1–6. The microarray from Study 36 has been deposited in GEO using accession no. GSE180677. RV144 data have been deposited in GEO at GSE103733. ALVAC comp data have been deposited in GEO with the accession no. GSE181996. P162 data have been deposited in GEO with the accession no. GSE72624. ChIP–seq data have been deposited in GEO with the accession no. GSE180749. Raw flow cytometry data have not been deposited but will be shared upon request.
Code availability
All code utilized for microarray, ChIP–seq and UMAP analysis will be made available to the public at https://github.com/sekalylab/Study36 and https://github.com/sekalylab/UMAP_Phenograph.
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Acknowledgements
We acknowledge A. Talla for generation of UMAP and Phenograph script for flow cytometry analysis; A. Trotch for assistance with running Meso Scale experiments; M. Vaccari for contribution of P162 data; the Yerkes NHP Genomics Core at Emory University for pooling and sequencing of ChIP–seq libraries; the veterinary staff who raised and cared for the animals used in Study 36 and P162; and the participants, clinical trial administrators and scientists who made RV144 possible. Study 36 was supported by Division of AIDS U19 grant AI067854 and UM1 grant AI100645 for the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID; B.H.); NIH, NIAID, Division of AIDS UM1 grant AI144371 for the Consortium for HIV/AIDS Vaccine Development (CHAVD; B.H.); the CCVIMC (OPP1032325) from the Bill and Melinda Gates Foundation (R.P.S. and R.K.); Harvard University Center for AIDS Research grant P30-AI060354; and New England Primate Research Center base grant OD011103. The Yerkes NHP Genomics Core is supported in part by NIH P51 OD011132 and sequencing data were acquired on an Illumina NovaSeq6000 funded by NIH S10 OD026799.
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Authors and Affiliations
Contributions
J.A.T. designed and performed experiments, analyzed data, generated figures and wrote the manuscript. A.N.P. performed all bioinformatic analysis of data, generated figures and edited the manuscript. S.F. contributed to data analysis and manuscript preparation. M.B.L. helped perform the ChIP–seq experiment. A.S. contributed to revisions and manuscript preparation. G.F. provided samples and guidance for the P162 validation. G.T. contributed to Study 36 design and execution, performed antibody measurements and edited the manuscript. R.P.S. aided in experimental design and setup, data analysis and generation of figures, and wrote the manuscript. B.H., N.L. and S.S. designed and carried out Study 36, and B.H. and S.S. edited the manuscript A.G., K.F., K.C., K.S., M.L., N.Y. and R.P. assisted with Study 36. J.T. provided ALVAC for studies. P.W. identified the initial CREB signature in Study 36. M.L.R., N.L.M. and R.K. provided guidance on study design.
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J.T. is an employee of Sanofi-Pasteur and provided the ALVAC vaccine components for all NHP and human studies. The other authors declare no competing interests.
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Peer review information Nature Immunology thanks Helder Nakaya and Shankar Subramaniam for their contribution to the peer review of this work. Peer reviewer reports are available. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Extended data
Extended Data Fig. 1 Study 36 design, vaccination schedule. sample collection strategy and bioinformatic analysis strategy.
a, NHP were immunized with ALVAC, empty insert [G1] or vCP1521 (HIV DNA encoding env, gag and pol)[G2], for two priming doses (Week 0 and 4) and two boosts along with recombinant Clade B/E gp120 (Week 12 and 23). PBMCs were isolated on Days 2/3 post Prime 1 (Week 0), 2 weeks post Prime 1 (Week 2) and 2 weeks post Boost 2 (Week 25) with DCs, CD4 + T cells and B cells purified by cell sorting. RNA was isolated from each cell type at each timepoint and microarray performed for transcriptional analysis. V1V2 IgG antibody titers were quantified at Week 14, Week 25, Week 53 and Week 55 post commencement of vaccine regimen. Additionally, plasma was isolated at the time of Prime 2 (Week 4) and 4 weeks post Boost 2 (Week 27). b, To identify TF target gene signatures which are associated with ALVAC immunogenicity, we implemented an analytical pipeline which generated independent GSEA analysis for each potential contrast (54 in total) in Study 36 in parallel and then identified those TF target gene signatures which were significant in all 3 cell types. First, we performed differential gene expression analysis of sorted DCs, CD4 + T cells and B cells by comparing post-vaccination timepoints (Week 0, Week 2 and Week 25) vs. pre-vaccination. GSEA using ChEA was performed on each of these 18 individual contrasts (3 cell types x 3 timepoints x 2 groups [G1,G2]) and this was termed ALVAC induced. Secondly, we correlated post-vaccination gene expression in the 3 sorted subsets (Week 0, Week 2 and Week 25) with IgG titers against V1V2 (Week 14, Week 25, Week 53 and Week 55). GSEA using ChEA was performed on each of these 36 individual contrasts (3 cell types x 3 microarray x 4 titers) and this was termed Correlate to V1V2. To identify TF target gene sets consistently ALVAC induced and correlating to V1V2, we intersect the 54 total GSEAs and highlighted TF target gene sets which were significant in all 3 cell types for ALVAC induction and correlation to V1V2.
Extended Data Fig. 2 IFN pathways are induced early in DCs and T cells but are not sustained during vaccination and do not correlate with V1V2 titers.
Upregulation of interferon signaling post-vaccination, compared to pre-vaccination, was determined for Group I and Group 2 in a, Dendritic cells and b, CD4+ T cells using preranked GSEA, without correction for multiple testing (p < 0.05). Induction of IFN pathways observed in both groups at Days 2/3 are absent by Week 25. In CD4 + T cells, only Group 2 shows upregulation of IFN and this response is only present at Days 2/3 suggesting that IFN upregulation post ALVAC vaccination is transient. N = 5 per group. A consolidated z-score generated for all IFN induced genes did not significantly correlate with V1V2 titers. Week 14 r = −0.7388, p = 0.154; Week 25 r = −0.3061, p = 0.6164; Week 55 r = −0.7993, p = 0.1046. c, To validate our GSEA findings in Study 36, we performed hypergeometric distribution testing. (Left) Significant enrichment of induced CREB1 target genes was observed for all 3 cell types at Weeks 0 and 2 in both G1 and G2. (Right) Significant enrichment of CREB1 target genes which correlate with V1V2 titers was found in all 3 cell types at Week 0 and Week 2 for the 4 titer timepoints measured. The lone exception was no significant enrichment for DCs at Week 0 to V1V2 titers at Week 53. These findings confirm our identification of CREB1 as ALVAC induced and a global correlate of V1V2.
Extended Data Fig. 3 ALVAC augments CREB1 driven gene expression by 24 hours post immunization and CREB1 signaling increases up to 72 hours post vaccination.
a, To more clearly understand the temporal nature of ALVAC induced CREB1, we accessed data from samples taken from the P162 study in which gene expression was quantified at 16, 24, 48 and 72 hrs after each of the 4 vaccination timepoints (n = 6 animals). GSEA using the CREB1 gene set from ChEA was performed to identify the temporal kinetics of ALVAC induced CREB1 by quantifying the fold induction of genes compared to pre-vaccination. In general, CREB1 target genes were suppressed at 16 hrs and induced at 24, 48 and 72 hrs. b, To determine if the same genes which were downregulated in some timepoints overlapped with those induced at others, a network was generated using Jaccard index to determine overlap in the CREB1 gene set leading edges for each of the timepoints. Red node color indicates induced, blue node color indicates suppressed. Node edge is colored per timepoint. Thickness of lines connecting nodes reflects the Jaccard index such that the thicker the line the more overlap. As can be seen, there is strong overlap by Jaccard index between the leading edges for the timepoints showing induced CREB1 target gene expression. By contrast, there is low overlap between blue nodes and red nodes indicating that the CREB1 target genes suppressed in the 4 timepoints are distinct from those induce at other timepoints.
Extended Data Fig. 4 CREB1 associated cytokine and chemokines in the plasma predict V1V2 titers and chemotaxis pathways are induced in Study 36.
a, Univariate correlations, using Pearson correlation, of Week 4 and Week 27 plasma cytokine levels to Week 53 and Week 55 V1V2 IgG. Statistical analysis performed using Pearson correlations (reported p.values. upper left: Eotaxin-3 = 0.0317, I-TAC = 0.017; upper right: Eotaxin-3 = 0.0457, IL-13 = 0.0199, IFNγ = 0.0094; lower right: GROα = 0.0187). b, Multivariate modeling using Lasso for Week 4 and Week 27 cytokines identifies combinatorial signatures of cytokines which strongly predict V1V2 titers. N = 5 animals from G2 arm of Study 36. c, In RV144, the individual participant z-scores of the cytokine/chemokine network from Fig. 2A was split into tertiles and associated with reduced HIV-1 acquisition using Log-rank test. Significantly reduced risk of HIV-1 acquisition was observed for the medium tertile (p = 0.005) along with substantial reduction in the high tertile (p = 0.10). d, GSEA analysis revealing ALVAC induced chemotactic signaling cascades in DCs, CD4 + T cell and B cells. e, GSEA analysis of GPCR signaling pathways in DCs and CD4 + T cells which correlate significantly with V1V2 titers. f, Subset specific distribution of cytokines and chemokines and their receptors which correlate, positively or negatively, with V1V2 titers in Study 36. Identifies common and unique cytokines/chemokines and their receptors among the 3 key immune subsets.
Extended Data Fig. 5 ChIP-seq confirms ALVAC induced CREB1 binding to immune genes in NHP and human PBMCs which overlap with transcriptional correlates of vaccine efficacy.
a, Venn diagram showing overlap between genes identified as enriched for CREB1 binding after ALVAC infection of NHP PBMCs and the ChEA CREB1 dataset. b, Bar plot showing significant overlap in genes identified by ChIP-seq as ALVAC induced in 2 or more of the infection conditions: empty ALVAC for 24 hrs, empty ALVAC for 48 hrs, ALVAC-HIV for 24 hrs and ALVAC-HIV for 48 hrs. c, Integrative Genomics Viewer (IGV) maps showing peaks of enriched CREB1 binding post ALVAC-HIV stimulation in the promoters of CX3CL1 (Fractalkine), CCL2 and Mamu-E, the NHP homolog of human HLA-E. d, Bar plot showing significant overlap between CREB1 genes identified as ALVAC induced, positive correlates of V1V2 in B cells from Study 36 and genes showing enriched CREB1 binding within 3 kB of their TSS in 1 or more of the ALVAC infection conditions by ChIP-seq. Significant overlap is observed for all combinations. e, In human PBMCs, enriched CREB1 binding was observed within 3kB of the TSS for the cytokine FLT3LG, antigen presentation gene HLA-DMB and TBK1 which is the kinase activated by STING. f, Venn diagram showing overlap between genes identified by ChIP-seq as enriched for CREB1 binding after 24 hr ALVAC infection of human PBMCs and ChEA CREB1 gene set. g, Bar plot of CREB1 target genes by ChIP-seq overlapped with the leading edge of CREB1 genes in RV144 which: 1) correlate with V1V2, 2) are induced post-vaccination or 3) are associated with reduced HIV-1 acquisition. Importantly, significant overlap is observed between CREB1 driven genes identified by ChIP-seq and CREB1 driven genes associated with reduced HIV-1 acquisition.
Extended Data Fig. 6 Genes and pathways reduced in MF59 are CREB1 driven and associated with reduced HIV acquisition in RV144.
a, GSEA analysis identifying immune related pathways which are significantly elevated in Alum compared to MF59 in P162. b, Network of the leading edge genes from pathways identified in Fig. 5d,e. Genes which are colored green are known CREB1 targets by ChEA and those in red are predicted CREB1 targets by promoter motifs. The majority of genes from these immune pathways are known or predicted targets of CREB1. c, The frequency of leading edge genes from the ALVAC induced CREB1 gene sets which correlate to V1V2 IgG titers was determined for all 3 cell subsets for all 12 contrasts (3 microarray timepoints compared to 4 V1V2 titers). The frequency of CREB1 driven genes which correlate to titers is significantly increased in all 3 cell subsets. This is true even for Week 25 microarray after antigen has been introduced into G1. Microarray timepoints (shapes): Circle = Week 0, Square = Week 2, Triangle = Week 25. V1V2 IgG titer timepoints: Black = Week 14, Red = Week 25, Blue = Week 53, Orange = Week 55. A two-sided Wilcoxon matched-paired signed rank test performed to compare frequency in G2 vs G1 paired at each individual contrast.
Extended Data Fig. 7 Manual FlowJo analysis confirms increased p-CREB + MFI and frequency in innate and adaptive immune cells.
a, p-CREB signal was quantified following treatment with Forskolin (n = 3), a known inducer of cAMP signaling, showing that p-CREB induction results in a shift in signal but is not bi-modal. b, Gating strategy for analysis. c, Histogram of p-CREB1 MFI in all cells and Clusters 5, 16, 17 and 20 showing higher p-CREB1 in these clusters compared to all cell. d, Density plots of UMAP analysis from Fig. 4 show that cGAMP induced p-CREB + populations are returned to basal levels after 60 minutes which is suggestive of true phospho-signaling. e, Representative histograms showing shift in p-CREB activity in total CD4 + T cells following 1 μM cGAMP stimulation for 15 m. f, Manual flow analysis of cGAMP treated samples (n = 5) in Fig. 4 confirms significant increases in p-CREB MFI for total CD4 + T cells, B cells, NK cells and other innate cells. Statistical analysis performed using a two-sided paired t-test. Line represents median and error bars are standard error of the mean.
Extended Data Fig. 8 Additional CREB1 related cytokines are induced in immune cells stimulated with cGAMP.
a, Median fold induction for all measured cytokines in purified DCs and CD4 + T cells treated with 10 uM cGAMP for 24 hours. b, TRAIL, GROα (CXCL1) and TGF-β1 which were all identified as positive correlates of V1V2 in Study 36 are also significantly induced by cGAMP treatment of purified DCs (black) and CD4 + T cells (blue) (n = 9), when these two groups are combined as distinct biological samples. Statistics performed using two-sided, paired t-test Lower line in violin plot is Q1, middle line is median and upper line is Q3. c, Proposed model of ALVAC induced CREB1 activation in mediating protective vaccine responses.
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Tomalka, J.A., Pelletier, A.N., Fourati, S. et al. The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination. Nat Immunol 22, 1294–1305 (2021). https://doi.org/10.1038/s41590-021-01026-9
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DOI: https://doi.org/10.1038/s41590-021-01026-9
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