Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MiRNA analysis after dendritic cell based therapeutic vaccination in HIV-1 infected individuals

ABSTRACT: Introduction: Systems vaccinology is a novel approach to predict immune response in vaccines. We have used a systems biology approach to identify early gene ‘signatures’ that predicted viral load control after analytical therapy interruption (ATI) in HIV-1 infected patients vaccinated with a dendritic cell-based (DC) HIV-1 vaccine. Methods: Frozen post-vaccination PBMC samples from participants of a previously published DC vaccine (DCV2) clinical trial were used for the study. mRNA and miRNA were extracted and gene expression was determined by microarray method. Differential gene expression analysis was performed on both mRNA and miRNA between responders (> 1 log10 copies/mL drop of VL after 12 weeks of ATI) and non-responders (<= 1 log10 copies/mL drop in VL at week 12 of ATI). Gene set enrichment analysis (GSEA) was carried out with the hallmark gene sets of the Broad Institute on the mRNA data. After the stand-alone analyses of mRNA and miRNA we performed an additional GSEA with gene sets defined by the genes regulated by significantly differentially expressed miRNAs. Statistical analysis was done using R and the GSEA software of the Broad Institute. Results: There were 15 responders and 20 non-responders. No differentially expressed mRNAs were observed between responders and non-responders. As compared with non-responders, responders showed an up-regulation of gene sets corresponding to TNF- alpha signaling via the NFkB pathway, inflammatory response, coagulation, the complement system, Il6 and Il2 JAK-STAT signaling, or reactive oxygen-species pathways were up-regulated, and a down-regulation of gene sets corresponding to E2F targets, oxidative phosphorylation, or interferon alpha response. We found 9 differentially expressed miRNAs between responders and non-responders: miR-32-3p, miR-185-3p, miR-223-3p, miR-500b-3p, miR-550a-3p, miR-1183, miR-1184, miR-4455, and miR-8063. Twelve Broad hallmark gene sets that were significantly deregulated in the GSEA showed significant overlap with genes regulated by one or more of these miRNAs, 10 of them with genes regulated by miR-223-3p. We also observed that the expression of genes regulated by miR-223-3p, miR-1183 and miR-8063 was significantly down-regulated in responders as compared with non-responders. Conclusions: Deregulation of certain gene sets related to inflammatory processes seems fundamental in viral control during ATI. miR-223-3p may be one of the miRNAs that fine tune part of these processes.

ORGANISM(S): Homo sapiens

SUBMITTER: Roque Pastor

PROVIDER: E-MTAB-10421 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Introduction: Systems vaccinology is a novel approach to predict immune response in vaccines. We have used a systems biology approach to identify early gene ‘signatures’ that predicted viral load control after analytical therapy interruption (ATI) in HIV-1 infected patients vaccinated with a dendritic cell-based (DC) HIV-1 vaccine. Methods: Frozen post-vaccination PBMC samples from participants of a previously published DC vaccine (DCV2) clinical trial were used for the study. mRNA and miRNA were extracted and gene expression was determined by microarray method. Differential gene expression analysis was performed on both mRNA and miRNA between responders (> 1 log10 copies/mL drop of VL after 12 weeks of ATI) and non-responders (<= 1 log10 copies/mL drop in VL at week 12 of ATI). Gene set enrichment analysis (GSEA) was carried out with the hallmark gene sets of the Broad Institute on the mRNA data. After the stand-alone analyses of mRNA and miRNA we performed an additional GSEA with gene sets defined by the genes regulated by significantly differentially expressed miRNAs. Statistical analysis was done using R and the GSEA software of the Broad Institute. Results: There were 15 responders and 20 non-responders. No differentially expressed mRNAs were observed between responders and non-responders. As compared with non-responders, responders showed an up-regulation of gene sets corresponding to TNF- alpha signaling via the NFkB pathway, inflammatory response, coagulation, the complement system, Il6 and Il2 JAK-STAT signaling, or reactive oxygen-species pathways were up-regulated, and a down-regulation of gene sets corresponding to E2F targets, oxidative phosphorylation, or interferon alpha response. We found 9 differentially expressed miRNAs between responders and non-responders: miR-32-3p, miR-185-3p, miR-223-3p, miR-500b-3p, miR-550a-3p, miR-1183, miR-1184, miR-4455, and miR-8063. Twelve Broad hallmark gene sets that were significantly deregulated in the GSEA showed significant overlap with genes regulated by one or more of these miRNAs, 10 of them with genes regulated by miR-223-3p. We also observed that the expression of genes regulated by miR-223-3p, miR-1183 and miR-8063 was significantly down-regulated in responders as compared with non-responders. Conclusions: Deregulation of certain gene sets related to inflammatory processes seems fundamental in viral control during ATI. miR-223-3p may be one of the miRNAs that fine tune part of these processes.

Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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MiRNA analysis after dendritic cell based therapeutic vaccination in HIV-1 infected individuals

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