Epigenetic Histone Landscape Profiles in HIV

HIV 中的表观遗传组蛋白景观谱

• 批准号: 10535173
• 负责人: PAUL JOSEPH UTZ
• 金额: $ 32.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535173
• 关键词: 2019-nCoV; AIDS clinical trial group; ATAC-seq; Adjuvant; Antigens; Attenuated; Autoimmunity; BCG Live; Bacteria; Blood Cells; CD14 gene; CD34 gene; COVID-19 vaccination; COVID-19 vaccine; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; ChIP-seq; Chromatin; Chronic; Communicable Diseases; Cryopreservation; Cytometry; DNA; DNA Vaccines; Data; Data Set; Dendritic Cells; Dengue; Elements; Enrollment; Epigenetic Process; Evolution; FCGR3B gene; Frequencies; Future; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Profile; Genes; Genetic Transcription; Goals; HIV; HIV Infections; HIV prevention trial; Hematopoietic stem cells; Histone Deacetylation; Histones; Human; Immune; Immunity; Immunization; Immunize; Immunoglobulin G; Immunologic Memory; Immunology; Impairment; Individual; Inflammatory; Influenza; Influenza vaccination; Innate Immune Response; Interferons; Leukapheresis; Link; Maps; Measurement; Measures; Memory; Messenger RNA; Methods; Myelogenous; Myeloid Cells; Natural History; Natural Immunity; Natural Killer Cells; Outcome; Paper; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Pfizer-BioNTech COVID-19 vaccine; Placebos; Plasma; Population; Post-Translational Protein Processing; Production; Research Personnel; Resistance to infection; Resolution; SIV; Sampling; Stains; System; T cell response; T-Lymphocyte; Testing; Time; Toll-like receptors; Training; Transcript; Transcription Factor AP-1; Vaccinated; Vaccination; Vaccinee; Vaccines; Validation; Virus; ZIKA; active method; antiviral immunity; arm; cytokine; epigenomics; influenza virus vaccine; innovation; monocyte; novel; preservation; response; seasonal influenza; simian human immunodeficiency virus; single cell analysis; transcriptomics; treatment arm; vaccine platform; vaccine trial

PROJECT SUMMARY/ABSTRACT The overarching goal of this R21 proposal is to test the hypothesis that DNA vaccines induce durable innate memory in HIV-infected humans by characterizing the evolution of the epigenetic and transcriptional landscape in subjects who have been immunized using a novel HIV DNA vaccine. We recently used a “systems immunology” approach to successfully map the epigenomic and transcriptional landscape of immunity to influenza vaccination in healthy humans. Vaccination against seasonal influenza, with or without AS03 adjuvant, resulted in persistently reduced expression of H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to toll like receptor (TLR) stimulation. Single cell analysis revealed an epigenomically-distinct subcluster of myeloid cells with reduced chromatin accessibility at activator protein-1 (AP-1) targeted loci after vaccination, persistently increased chromatin accessibility at loci targeted by interferon (IFN) response factors (IRFs), which was associated with elevated expression of antiviral genes, type 1 IFN production, and heightened resistance to infection with the heterologous viruses Zika and dengue. In another recent paper, we have shown that the Pfizer-BioNTech mRNA prime-boost vaccine (BNT162b2) resulted in enhanced innate immune responses, evidenced by a greater frequency of CD14+CD16+ inflammatory monocytes, higher plasma IFN-γ, and a transcriptional signature of innate antiviral immunity. We will replicate this “systems immunology” framework to characterize innate memory using peripheral blood mononuclear cells (PBMCs) from HIV+ subjects in the A5369 prime-boost DNA vaccine trial (NCT03560258). Induction and durability of innate memory will be studied across 3 aims in this R21. Aim 1 will identify histone posttranslational modifications (HPTMs) in PBMCs at single-cell resolution using Epigenetic Landscape Profiling using Cytometry by Time Of Flight (EpiTOF). We will test the hypothesis that antigen-specific DNA vaccination induces innate memory through epigenetic reprogramming, expands with each sequential prime and boost (week 0 < week 6 << week 26), and is preserved at week 48. Aim 2 will identify gene transcript modules, and their evolution over time, associated with innate memory. We will test the hypothesis that antigen-specific DNA vaccination induces durable innate memory through transcriptomic changes and expands with each sequential prime and boost (week 0 << week 26 > week 48). We will test the hypothesis that transcriptional modules that characterize innate memory in influenza and SARS-CoV-2 vaccination are generalizable to HIV DNA vaccines. We also expect to identify unique subsets of cells, transcripts, and pathways associated with innate memory that differ from influenza and SARS-CoV-2. Aim 3 will perform systems immunology analysis by integrating EpiTOF and transcriptomic data from Aims 1 &2, and comparing with similar data from influenza and SARS-CoV-2 vaccinated subjects testing the hypothesis that there are generalizable mechanisms underlying innate memory across vaccine platforms, and cells and pathways specific to DNA vaccines and/or HIV infection.

项目总结/文摘