Methylation profiles predict ATI outcome in the kick-and-kill therapeutic vaccine BCN02 clinical trial [450K]
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ABSTRACT:
PROVIDER: PRJNA769210 | ENA |
REPOSITORIES: ENA
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Project description:BCN02 was an exploratory, single arm study designed to evaluate a kick-and-kill therapeutic vaccine strategy in early-treated HIV infected individuals. The participants in the study received a MVA.HIVconsv vaccination before and after three cycles of infusion of romidepsin (RMD), an inhibitor of histone deacetylases that acts as a viral latency reversing agent. The inclusion of a monitored antiretroviral pause (MAP) identified 8 individuals with an early viral rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a late viral rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study, a systems biology analysis was conducted to identify the pathways modulated at transcriptomic and epigenetic level during the clinical intervention, involving vaccination and RMD, and to identify biomarkers predictive of HIV viral rebound during MAP. To this end, we studied gene expression and whole-genome DNA methylation in longitudinal PBMC samples prior and after the intervention. The main impact on host transcriptional and epigenetic signatures was observed after vaccination and RMD infusion (Vacc+RMD) with multiple pathways related to HIV infection and immune response showing changes at gene expression and DNA methylation level. Analysis of an independent cohort of individuals treated with RMD alone, showed that these changes were mainly driven by CD4 T cells. DNA methylation patterns in full PBMC obtained after full intervention (Vacc+RMD) allowed to discriminate individuals with an Early versus Late viral rebound. These individuals also showed a differential enrichment on chromatin accessibility and transcription factor binding sites. Intriguingly, 30 of the DMPs between Early and Late rebounders at Vacc+RMD were present already at baseline and were more accentuated after RMD infusion. Overall, this study provides with a deeper understanding of the mechanisms modulated during the BCN02 study and highlights the importance of DNA methylation profiles in HIV cure.
2022-03-28 | GSE185389 | GEO
Project description:Methylation profiles predict ATI outcome in the kick-and-kill therapeutic vaccine BCN02 clinical trial
| PRJNA769058 | ENA
Project description:Methylation profiles predict ATI outcome in the kick-and-kill therapeutic vaccine BCN02 clinical trial [EPIC array]
| PRJNA769211 | ENA
Project description:BCN02 was an exploratory, single arm study designed to evaluate a kick-and-kill therapeutic vaccine strategy in early-treated HIV infected individuals. The participants in the study received a MVA.HIVconsv vaccination before and after three cycles of infusion of romidepsin (RMD), an inhibitor of histone deacetylases that acts as a viral latency reversing agent. The inclusion of a monitored antiretroviral pause (MAP) identified 8 individuals with an early viral rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a late viral rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study, a systems biology analysis was conducted to identify the pathways modulated at transcriptomic and epigenetic level during the clinical intervention, involving vaccination and RMD, and to identify biomarkers predictive of HIV viral rebound during MAP. To this end, we studied gene expression and whole-genome DNA methylation in longitudinal PBMC samples prior and after the intervention. The main impact on host transcriptional and epigenetic signatures was observed after vaccination and RMD infusion (Vacc+RMD) with multiple pathways related to HIV infection and immune response showing changes at gene expression and DNA methylation level. Analysis of an independent cohort of individuals treated with RMD alone, showed that these changes were mainly driven by CD4 T cells. DNA methylation patterns in full PBMC obtained after full intervention (Vacc+RMD) allowed to discriminate individuals with an Early versus Late viral rebound. These individuals also showed a differential enrichment on chromatin accessibility and transcription factor binding sites. Intriguingly, 30 of the DMPs between Early and Late rebounders at Vacc+RMD were present already at baseline and were more accentuated after RMD infusion. Overall, this study provides with a deeper understanding of the mechanisms modulated during the BCN02 study and highlights the importance of DNA methylation profiles in HIV cure.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:The BCN02 (NCT02616874) was a pilot study to evaluate the kick and kill therapy on 15 early-treated individuals that were rolled-over from the BCN01 Study. The participants in the study received two MVA.HIVconsv vaccination before and after the 3-cycle infusion of Romidepsin, an inhibitor of histone deacetylases that act as a latency reversing agent. Additionally, the inclusion of a monitored antiretroviral pause (MAP) allowed tthe identification of 8 individuals with an Early Rebound (pVL > 2,000 HIV RNA copies/mL, < 4 weeks of MAP initiation) and 4, with a Late Rebound (pVL > 2,000 HIV RNA copies/mL, > 4 weeks of MAP initiation). In the present study we studied gene expression at 3 different timepoints: w0 (Bsl), w1 (Vacc), w6 (Vacc+RMD) and applied pairwise comparisons.
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Project description:PBMC Gene expression of participants in the kick and kill clinical trial BCN02
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Project description:In this study, we present a novel hybrid data-independent acquisition LC-MS approach, combining QconCAT technology with short microflow LC gradients and DIA and apply the method towards the quantitative proteome analysis of ATI extracts from wheat flour. The novel method is fast, robust and reproducible and provides accurate QconCAT-based absolute quantification of major ATI proteins while simultaneously quantifying the non-targeted proteome by DIA-based label-free quantification. Using a set of 120 samples of full kernel flour derived from 60 varieties of common wheat grown in replication, we assess the repeatability and accuracy of the workflow for the quantification of ATI at the peptide and protein level. Applying the method to analyze different wheat species (i.e. common wheat, spelt, durum wheat, emmer and einkorn) and comparing the results to published data, we validate inter-laboratory and cross-methodology reproducibility of ATI quantification, which are essential in the context of large-scale breeding projects. Additionally, we apply our workflow to assess environmental effects on ATI expression, analyzing ATI content and proteome of wheat species grown at different locations. Finally, we explore the potential of combining QconCAT-based absolute quantification with DIA-based untargeted proteome analysis and LFQ for the generation of new hypotheses or assay development.
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