SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design

SHIV Env-抗体协同进化作为 HIV-1 V3 聚糖靶向疫苗设计的分子指南

基本信息

  • 批准号:
    10631866
  • 负责人:
  • 金额:
    $ 410.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-03-07 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The development of an effective HIV-1 vaccine has proven to be a daunting scientific challenge. Despite decades of research, there are no examples of immunogens that consistently elicit potent broadly neutralizing antibodies (bNAbs). Our scientific premise is that there are three principal obstacles to inducing bNAbs in primates and humans that prior vaccine approaches have largely failed to overcome. These are: i) efficient and consistent priming of multiple HIV-1 bNAb precursor B cells; ii) immunofocused boosting of B cell responses targeting conserved bNAb epitopes and away from off-target epitopes; and iii) affinity-guided maturation of B cell lineages to select for enhanced neutralization breadth and potency. Here, we address each of these requirements. This application is a competitive renewal of an existing HIVRAD award where we hypothesized that a major roadblock to rational HIV-1 vaccine design is the lack of a suitable primate model in which bNAbs can be commonly induced and the molecular, biological and immunological mechanisms responsible for such responses studied in a reproducible and iterative fashion. Overcoming this roadblock was one of the major goals of that grant, and over the past five years we have made substantial progress in reaching this milestone. We did this by developing a novel design strategy for creating simian-human immunodeficiency viruses (SHIV) that bear clinically-relevant primary HIV-1 Envs and that replicate efficiently in rhesus macaques (RMs). We next hypothesized that SHIV- infected RMs could be used to identify HIV-1 Envs that have a propensity for eliciting bNAbs of predetermined epitope specificity, thus allowing for a detailed and reproducible molecular characterization of the coevolutionary pathways of Env and Ab that lead to affinity maturation and breadth. Again, we obtained strong supporting evidence (Science 371:eabd2638, 2021). Here we propose to build on this foundation and to test the hypothesis that elucidation of the molecular pathways of Env-Ab coevolution leading to neutralization breadth in SHIV- infected RMs, combined with biophysical and immunological analyses of key Env-Ab lineage intermediates, can provide a molecular “blueprint” for successful germline-targeted, B cell lineage-based immunogen design. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs (Shaw); Project 2 - Optimizing humoral immunity to HIV-1 Env proteins (Kelsoe); Project 3 - Immunogen design to elicit polyclonal bNAb responses to the V3 glycan supersite (Wiehe). These projects will be enabled by Core A – Administrative (Shaw); Core B – Viral and antibody gene sequencing (Hahn); and Core C – Bioinformatics and statistics (Wagh). The significance of the proposed studies is potentially far-reaching: previous studies of HIV-1 SOSIP Env trimer vaccinations have generally elicited only autologous strain-specific Nab responses in outbred animals. If we can demonstrate consistent induction of bNAbs using germline-targeted, lineage-based SOSIP Env trimers as immunogens in RMs, it would represent a major scientific advance and a new beachhead for HIV-1 vaccine research.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

GEORGE M SHAW其他文献

GEORGE M SHAW的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('GEORGE M SHAW', 18)}}的其他基金

Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
  • 批准号:
    10577775
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
  • 批准号:
    10624301
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
  • 批准号:
    10370383
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
  • 批准号:
    10437032
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies
HIV-1 Q23.17 Env:设计一种新型免疫原以引发广泛中和抗体
  • 批准号:
    10326691
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
Reverse Vaccinology in SHIV Infected Macaques as a Molecular Guide for HIV-1 Vaccine Design
SHIV 感染猕猴的逆向疫苗学作为 HIV-1 疫苗设计的分子指南
  • 批准号:
    10224528
  • 财政年份:
    2021
  • 资助金额:
    $ 410.48万
  • 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
  • 批准号:
    9316783
  • 财政年份:
    2017
  • 资助金额:
    $ 410.48万
  • 项目类别:
Env evolution in humans and RMs
人类和 RM 的环境进化
  • 批准号:
    10117175
  • 财政年份:
    2017
  • 资助金额:
    $ 410.48万
  • 项目类别:
Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs
SHIV 感染 RM 中的 Env-Ab 共同进化导致 V3 聚糖 bNAb
  • 批准号:
    10370983
  • 财政年份:
    2017
  • 资助金额:
    $ 410.48万
  • 项目类别:
SHIV/HIV Env-Antibody Coevolution as a Guide to Iterative Vaccine Design
SHIV/HIV 包膜抗体协同进化作为迭代疫苗设计的指南
  • 批准号:
    10117167
  • 财政年份:
    2017
  • 资助金额:
    $ 410.48万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 410.48万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了