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

PROVIDER: PRJNA780552 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16951630_1.fastq.gz	Fastqsanger.gz
	SRR16951630_2.fastq.gz	Fastqsanger.gz
	SRR16951631_1.fastq.gz	Fastqsanger.gz
	SRR16951631_2.fastq.gz	Fastqsanger.gz
	SRR16951632_1.fastq.gz	Fastqsanger.gz

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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.

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

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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.

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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.

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