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ATAC-seq profiling in CD14+ cells isolated from rhesus macaques vaccinated with V1-deleted DNA/ALVAC/gp120 vaccine [study 2]

ABSTRACT: We analyzed innate and adaptive immune responses elicited by the V1-deleted DNA/ALVAC/gp120/alum vaccine in non-human primates. Following SIVmac251 challenge exposure, we observed reduced risk of SIV acquisition comparing vaccinated animals to controls, confirming th ability of this vaccine strategy in decreasing the risk of SIV acquisition against vaginal exposure. Transcriptome and chromatin accessibility in CD14+ cells were analyzed by RNA-seq and ATAC-seq. Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway correlated with vaccine efficacy. The efficacy of V1-delted DNA/ALVAC/gp120/alum vaccine, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Our data support the protective role for CREB1 expression in monocytes and posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE188879 | GEO | 2023/01/06

REPOSITORIES: GEO

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RNA-seq profiling in CD14+ cells isolated from rhesus macaques vaccinated with V1-deleted DNA/ALVAC/gp120 vaccine

Project description:We analyzed innate and adaptive immune responses elicited by the V1-deleted DNA/ALVAC/gp120/alum vaccine in non-human primates. Following SIVmac251 challenge exposure, we observed reduced risk of SIV acquisition comparing vaccinated animals to controls, confirming th ability of this vaccine strategy in decreasing the risk of SIV acquisition against vaginal exposure. Transcriptome and chromatin accessibility in CD14+ cells were analyzed by RNA-seq and ATAC-seq. Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway correlated with vaccine efficacy. The efficacy of V1-delted DNA/ALVAC/gp120/alum vaccine, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Our data support the protective role for CREB1 expression in monocytes and posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.

2023-01-06 | GSE189032 | GEO

Transcriptomic profiling of rhesus macaques vaccinated with ALVAC-SIV/gp120 adjuvanted in Alum or MF59.

Project description:The Canarypox/gp120/Alum vaccines decreased the risk of HIV acquisition in humans. We demonstrate here the efficacy of this vaccine regimen also in the SIVmac251 macaque model when we used the alum but not the MF59 adjuvant. Analysis of innate and adaptive cell responses, envelope antibodies Fc profiles and glycoforms demonstrated a lower inflammatory response with alum than MF59. Alum elicited mucosal V2 peptide-specific IgG associated with vaccine efficacy whereas the MF59 induced mucosal V2 peptide-specific IgG associated with increased risk of infection. Alum modulated the expression of 12 genes, 7 of which are part of the RAS pathway, that correlates with vaccine efficacy and were linked to innate responses that preserve mucosal integrity and adaptive mucosal antibody response to V2. Thus, activation of the RAS pathway, preservation of mucosal integrity and mucosal antibody to V2 in concert, reduce the risk of SIVmac251 acquisition. Fifty-four (54) rhesus macaques were randomized into two vaccination groups. One group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in MF59 adjuvant (at week 12 and week 24). The second group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in Alum adjuvant (at week 12 and week 24). Blood samples were taken pre-vaccination, 24 hours after the first prime (post-1st imunization at week 0) and 24 hours after the first boost (post-3rd immunization at week 12). All the samples were taken before SIV challenge. Blood samples were conserved in PAXgene tubes. RNA was extracted and hybridized to Illumina beadchips. technical replicate: P162_P382_post1st, P162_P382_post1st_rep1

2016-05-29 | E-GEOD-72624 | biostudies-arrayexpress

Transcriptomic profiling of young and old rhesus macaques vaccinated with DNA/ALVAC+gp120

Project description:The development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to the virus. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Central to vaccine efficacy is the engagement of the CCR2+/CCL2 axis and tolerogenic dendritic cells producing IL-10 (DC-10). Durable epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway and increased levels of miRNA-139-5p, a negative regulator of expression of the cAMP-specific phosphodiesterase PDE4D, in extracellular vesicles correlated with vaccine efficacy. These data posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.

2022-12-28 | GSE188901 | GEO

Transcriptomic profiling of rhesus macaques vaccinated with Ad26/ALVAC+gp120 or DNA/ALVAC+gp120

Project description:We contrasted innate and adaptive immune responses of HIV vaccine candidates of varying efficacy in macaques that shared the ALVAC+gp120 protein boost with an ALVAC, DNA or Ad26 prime modality. The vaccine efficacies of the DNA/ALVAC+gp120 and ALVAC/ALVAC+gp120 vaccine regimens, both protective, were associated with qualitative temporal-spatial differences in the innate CD14+ and CD16+ cells in blood and tissues. The activation of hypoxia and the inflammasome in CD14+ DR+ CD16- classical monocytes and CD4+ Th2 responses correlated with a decreased risk of SIVmac251 acquisition. CD4+ Th2 cells, in turn, correlated with mucosal NKp44+ cells and mucosal protective antibodies to V2. In contrast, the Ad26/ALVAC+gp120 vaccine resulted in increased de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes, increased CD4+ Th17 cells in blood and rectal mucosa, and a lack vaccine efficacy. These data posit that the engagement of classical monocytes and inflammasome activation is central for the elicitation of protective innate and adaptive responses by the ALVAC-based HIV vaccine platform.

2018-02-23 | GSE108011 | GEO

Transcriptional profiling of macaques treated with ALVAC- and NYVAC-SIV+gp120 alum vaccines

Project description:We compare the immunogenicity of ALVAC- or NYVAC- based SIVmac251 vaccine regimens combined with gp120/alum boosts and their relative efficacy in a cohort of 65 female rhesus macaques. Both NYVAC- and ALVAC-based regimens induced equivalent titers of serum binding antibodies to gp120, whereas NYVAC elicited significantly higher envelope specific T cell responses. Surprisingly, however, only the ALVAC-based regimen was able to significantly decrease the risk of SIVmac251 acquisition following repeated low-dose intravaginal challenges. The risk of virus acquisition was associated negatively with the frequency of classical monocytes and positively with non-classical. The systems biology approach used to investigate the molecular basis of the different vaccine efficacies demonstrated specific expression profiles elicited by the ALVAC-based regimen that correlate with efficacy.

2020-03-05 | GSE138195 | GEO

Transcriptomic profiling of rhesus macaques vaccinated with ALVAC-SIV/gp120 adjuvanted in Alum or MF59.

2016-05-29 | GSE72624 | GEO

Transcriptional profiling of macaques treated with ALVAC- and NYVAC-SIV+gp120 alum vaccines

Project description:Transcriptional profiling of macaques treated with ALVAC- and NYVAC-SIV+gp120 alum vaccines

| PRJNA575064 | ENA

MicroRNA profiling of extracellular vesicles isolated from rhesus macaques vaccinated with DNA/ALVAC/gp120 vaccine

Project description:We contrasted innate and adaptive immune responses elicited by the DNA/ALVAC/gp120/alum vaccine in non-human primates differing in age. We performed several analyses. MicroRNA profiling in Extracellular Vesicles (EVs) isolated from plasma collected prior and 1 week following vaccination identified 109 miRNAs that differed significantly between age groups at the end of immunization. Several miRNAs correlated with risk of virus acquisition in young and old animals, but none remained significant following correction for FDR. In young animals, we identified 3 miRNAs which were modified by vaccination and correlated with decreased risk of SIV acquisition (unadjusted p-values). Of these three miRNAs, two, miR-139-5p and miR-29b-1-5p, were increased by vaccination, whereas one, mir 98, decreased by vaccination. MiR-139-5p has several validated targets, including: CXCR4, important for egress of CXCR4+ cells and monocytes from bone marrow and HIV entry in target T-cells; the cAMP-specific PDE4D gene which decreases CREB1-mediated transcription by degrading cAMP; and the IGF-1/AKT/Glut1 gene receptor, central for glucose utilization and cellular metabolism. The validated target of miR-29b-1-5p is the NF-kB pathway. Mir-98 has several validated targets, inhibits IL-10 production, modulates M1-M2 polarization of macrophages towards the M1 phenotype, and its CCL2-induced downregulation increases IL-6 production. These data suggest the importance of CREB1-mediated transcription in vaccine efficacy, identified in the study, is likely assisted by miR-139-5p targeting the cAMP-degrading PDE4D gene, and downregulation of the NF-kB pathway, targeted by miR-29b-1-5p.

2023-01-06 | GSE188575 | GEO

Transcriptomic profiling of rhesus macaques vaccinated with Ad26/ALVAC+gp120 or DNA/ALVAC+gp120

Project description:Transcriptomic profiling of rhesus macaques vaccinated with Ad26/ALVAC+gp120 or DNA/ALVAC+gp120

| PRJNA422217 | ENA

Microarray analysis to identify optimal timepoint post-ALVAC vaccintation to investigate innate immune pathways

Project description:ALVAC-Comp was an NHP immunogenicity study designed to identify the temporal kinetics of innate immune activation by ALVAC-SIV vaccination. PAXGENE tubes were harvested at 16h, 24h, 48h and 72h post vaccination to investigate the speed, magnitude, and durability of ALVAC-SIV induced innate immune activation. This study was set up to identify the optimal timepoint(s) post-vaccination in which to probe the cellular and molecular signaling mechanisms of innate immunity induced by vaccination. Comparison of genes/pathways in common and unique to the 4 post-vaccination timepoints will reveal the order of innate immune induction post-vaccination.

2021-08-13 | GSE181996 | GEO

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