NOVEL ADENOVIRUS-VECTORED HIV VACCINE THAT KNOCKS THE SOCS1 OFF DENDRITIC CELLS

新型腺病毒载体 HIV 疫苗可敲除树突状细胞上的 SOCS1

• 批准号: 8172421
• 负责人: Jerry L Blackwell
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172421
• 关键词: Adenovirus Vector; Adenoviruses; Adjuvant; Antigen Presentation; Antigens; Attenuated; Bone Marrow; CD8B1 gene; Computer Retrieval of Information on Scientific Projects Database; Cytokine Inducible SH2-Containing Protein; Dendritic Cells; Development; Funding; Grant; HIV-1; Immune response; Infection; Institution; Macaca mulatta; Mediating; Messenger RNA; Mus; Phosphorylation; Proteins; Receptor Signaling; Research; Research Personnel; Resources; Role; STAT1 gene; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; System; T cell response; T-Lymphocyte; Testing; Toll-like receptors; Transcription Coactivator; Transducers; Transgenes; United States National Institutes of Health; Vaccinated; Vaccines; Work; base; design; improved; in vivo; novel; protein function; response; vaccine candidate; vaccine efficacy; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Efforts aimed at stimulating immune responses by modifying Human Immunodeficiency virus-1 (HIV) antigens and using a variety of delivery systems and adjuvants have so far failed to produce an HIV vaccine that protects against primary infections, highlighting the need for the continued development of alternative and effective vaccine candidates. Our project is based on findings that the suppressor of cytokine signaling 1 (SOCS1) protein functions as an antigen-presentation attenuator by restricting the Janus-activated kinasesignal transducers and activators of transcription and Toll-like receptor-signaling pathways. To test this hypothesis, the Specific Aims of the project are to: 1) Inhibit DC SOCS1 expression with Ad-mediated delivery of SOCS1 siRNA 2) Determine the effect(s) of SOCS1-silencing on DC function 3) Evaluate the HIV-specific immunes responses induced by SOCS1-silencing Ad-vectored vaccines We have made the following progress during this funding period: + Developed adenovirus vectors that co-express siRNA that target mouse SOCS1 mRNA and transgenes + Demonstrated the SOCS1 siRNA silencing reduced the expression of SOCS1 protein levels in mouse bone marrow-derived mouse dendritic cells + Demonstrated that SOCS1 siRNA-silencing extends the duration of STAT1 phosphorylation as a result of induction by LPS and INF-gamma signaling in bone marrow-derived mouse dendritic cells + Pilot test of the SOCS1-silencing adenovirus vectors demonstrated enhanced antigen-specific CD8+ T cells responses in vivo + Observed higher levels of adenovirus-specific CD8+ T cells in mice vaccinated with SOCS1-silencing vectors + Generated three adenovirus vectors that express SOCS1 siRNAs that target rhesus macaque SOCS1 mRNA The significance of our progress is in the development of a novel adenovirus vector platform designed to directly modulate the immune responses induced by the vaccine. Moreover, the work thus far suggests that by attenuating the down-regulatory role of SOCS1 during the induction of immune responses will serve to significantly improve the vaccine efficacy.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 旨在通过修改人类免疫缺陷病毒1（HIV）抗原以及使用各种递送系统和佐剂来刺激免疫反应的努力，迄今未能产生一种艾滋病毒疫苗，以防止原发性感染，强调需要持续开发替代性和有效疫苗候选者。我们的项目基于发现，细胞因子信号传导1（SOCS1）蛋白的抑制剂通过限制了JANUS激活的激酶信号透射剂和转录和TOLL样受体 - 受体信号信号途径的激活剂，通过限制了JANUS激活的激酶信号传感器和激活剂来充当抗原呈递衰减剂。为了检验这一假设，该项目的具体目的是： 1）通过AD介导的SOCS1 siRNA抑制DC SOCS1表达 2）确定SOCS1沉默对直流功能的影响 3）评估由SOCS1沉默的Ad-Vectored疫苗引起的HIV特异性免疫反应 在此资助期间，我们取得了以下进展： +开发了腺病毒载体，该载体是靶向小鼠SOCS1 mRNA和转基因的共表达siRNA +证明了SOCS1 siRNA沉默可降低小鼠骨髓衍生的小鼠树突状细胞中SOCS1蛋白水平的表达 +证明SOCS1 siRNA沉淀扩大了由于LPS和骨髓衍生的小鼠树突状细胞中LPS和INF-GAMMA信号传导的诱导而扩大了STAT1磷酸化的持续时间 + SOCS1沉默腺病毒载体的试验测试表明，体内抗原特异性CD8+ T细胞反应增强 +观察到的较高水平的腺病毒特异性CD8+ T细胞在接种SOCS1-SELENCED载体的小鼠中 +产生了三个表达SOCS1 siRNA的腺病毒矢量 我们进步的意义在于开发新型腺病毒矢量平台，旨在直接调节疫苗诱导的免疫反应。 此外，迄今为止的工作表明，通过减轻SOCS1在诱导免疫反应期间的下调作用，将显着提高疫苗功效。