Structures of initial CD4 engagement with pre-fusion, closed HIV-1 Envelope trimer and early CD4-induced conformational changes required for infection
初始 CD4 与融合前接合的结构、封闭的 HIV-1 包膜三聚体以及感染所需的早期 CD4 诱导的构象变化
基本信息
- 批准号:10090565
- 负责人:
- 金额:$ 73.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAlgorithmsAntibodiesAntigensBindingCD4 AntigensCD4 Positive T LymphocytesComplexCryoelectron MicroscopyDataData CollectionDrug DesignEngineeringEpitopesEventGoalsGrantHIV-1HIV-1 vaccineImmunodominant EpitopesInfectionInterventionMediatingMethodsMicroscopeMolecular ConformationMovementMutationPathway interactionsPeptidesPharmaceutical PreparationsPreparationProtomerResolutionSamplingSideSiteSpecimenStructureTechniquesTechnologyVaccinesVirionVirusVisualizationbasecomputerized data processingdesignexpectationexperimental studyimprovedinnovationmolecular dynamicsmovieneutralizing antibodynovelpreventsingle-molecule FRETtherapeutic developmenttherapy developmenttime usevaccine development
项目摘要
The initial contact site of the CD4 receptor on pre-fusion, closed HIV-1 envelope (Env) trimer is highly
conserved, and is targeted by neutralizing antibodies. This site is an important target for vaccine and
therapeutics development. Structural definition of this initial interaction has been a challenge because
conformational changes in the HIV-1 Env trimer follow immediately upon CD4 engagement. There are no high
resolution structures of the initial contact of the pre-fusion, closed HIV-1 Env trimer with CD4. The structural
details of the conformational changes that follow immediately upon CD4 binding are also not known. Precise
definition of initial CD4 contacts with the closed HIV-1 Env trimer will fill a gap in our understanding of this early
event in HIV-1 entry, and will provide atomic level information for structure-based immunogen design. The
overall goals of this study, therefore are, (i) to define, at atomic level details, the initial site of CD4 binding on
pre-fusion, closed HIV-1 Env trimer, (ii) to define the steps leading to CD4-induced protomer opening, and (iii)
to elucidate CD4-mediated changes in the HIV-1 fusion peptide, an immunodominant region critical for
mediating HIV-1 CD4+ T cell entry, and itself a target of neutralizing antibodies. The scientific premise of this
grant is that the initial contact of CD4 with HIV-1 Env is the critical first step that determines virus attachment.
Although CD4 can bind to multiple Env conformations, this first site of contact on the HIV-1 Env trimer is the
target of broadly neutralizing antibodies and effective drugs, hence high resolution structural details of this
interaction and a mechanistic understanding of subsequent conformational changes will facilitate the
development of intervention strategies that include immunogen design for HIV-1 vaccine efforts and drug
design for novel cure AIDS strategies to eliminate the latent pool of HIV-1-infected CD4 T cells. The
innovation in this grant derives from advances in cryo-EM technology that include new grid preparation and
specimen vitrification methods, improved microscope hardware, automated methods for high-throughput data
collection, and advanced algorithms for data processing. These advances have recently allowed us to
establish a rapid pipeline for determining high resolution structures of HIV-1 Env complexes. The innovation
also derives from availability of panels of native-like Env constructs and antibodies for the proposed structural
and mechanistic analyses. At the completion of this study we expect to provide a movie for CD4-induced
opening of the HIV-1 Env trimer. High resolution structures of the initial CD4 contact on the closed HIV-1 Env
trimer will provide atomic level information for structure-based immunogen and drug design. Visualization of
the initial steps of CD4-induced Env opening will provide information on which Env regions move first, and will
inform the design of stabilized immunogens. This study will also provide an understanding of the CD4-induced
conformational diversity sampled at the HIV-1 fusion peptide region and how antibodies, both natural and
vaccine-elicited, respond to it.
CD4受体在融合前闭合的HIV-1包膜(Env)三聚体上的初始接触位点高度
项目成果
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Priyamvada Acharya其他文献
Priyamvada Acharya的其他文献
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{{ truncateString('Priyamvada Acharya', 18)}}的其他基金
Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike
自然和工程变异对 SARS-CoV-2 刺突结构和生物物理学的影响
- 批准号:
10558637 - 财政年份:2022
- 资助金额:
$ 73.92万 - 项目类别:
Project 3 - Dynamics of latent HIV-1 reservoirs: High resolution antigenic mapping and strategies to block rebound
项目 3 - 潜在 HIV-1 储存库的动态:高分辨率抗原图谱和阻止反弹的策略
- 批准号:
10506669 - 财政年份:2022
- 资助金额:
$ 73.92万 - 项目类别:
Dissecting the mechanisms of HIV resistance in vivo to broadly neutralizing antibodies
剖析 HIV 体内对广泛中和抗体的耐药机制
- 批准号:
10458981 - 财政年份:2022
- 资助金额:
$ 73.92万 - 项目类别:
Dissecting the mechanisms of HIV resistance in vivo to broadly neutralizing antibodies
剖析 HIV 体内对广泛中和抗体的耐药机制
- 批准号:
10680388 - 财政年份:2022
- 资助金额:
$ 73.92万 - 项目类别:
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