CCR5 determinants for the HIV transmitted founder phenotype

HIV 传播创始人表型的 CCR5 决定因素

基本信息

批准号：
10760884
负责人：
Anthony L DeVico
金额：
$ 23.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760884
关键词：
3-Dimensional AIDS prevention Address Affinity Amino Acid Sequence Anti-Retroviral Agents Binding CCR5 gene CD4 Positive T Lymphocytes Cell surface Cells Characteristics Comparative Study Data Data Set Development Dimerization Down-Regulation Drug Targeting Early Diagnosis Environment Exposure to Fluorescence Resonance Energy Transfer GTP-Binding Proteins Genotype Goals HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine Human In Situ In Vitro Individual Infection Intervention Knowledge Ligands Link Lymphocyte Macrophage Measures Mediating Membrane Methods Molecular Monoclonal Antibodies Nature Open Reading Frames Phenotype Population Prevention Productivity Proteins Reagent Receptor Signaling Recycling Reporting Resistance Resolution Role SIV Signal Transduction Sorting Structure Sulfate Surface Testing Translating Vaccine Design Viral Genes Viral Proteins Virus Virus Diseases Virus Replication antagonist cell type chemokine chronic infection detection sensitivity env Gene Products experimental study humanized mouse imaging approach imaging modality immunoreactivity in vivo innovation monocyte mutant nef Protein optical imaging pressure prevent receptor simian human immunodeficiency virus superresolution imaging transmission process ultra high resolution virus envelope

项目摘要

ABSTRACT HIV is naturally transmitted as a virus swarm, which establishes infection via only one or few transmitted/founder (T/F) viruses. Several observations strongly indicate that T/F viruses are non-randomly favored for productive transmission via shared signature genotypic and phenotypic characteristics. Current knowledge regarding Env- coreceptor interactions suggest innovative concepts to explain the T/F phenotype. T/F virus envelopes of all subtypes preferentially use the CCR5 coreceptor for entry in vitro and in vivo. Yet cell surface CCR5 is expressed in multiple functional and antigenic forms with differential sensitivity to the antiretroviral CCR5 antagonist maraviroc (MVC); affinity for natural chemokine ligands, and/or reactivity with anti-CCR5 monoclonal antibodies (mAbs). Further, the abilities of various anti-CCR5 mAbs to inhibit CCR5 interactions with either tagged soluble gp120s or pseudoviruses vary according to virus strain and target cell-type. Collectively, these findings prompt the central hypothesis for this exploratory project: as a class, T/F viruses utilize signature CCR5 subpopulation(s) that potentially favor more efficient entry and virus replication. Tests of this hypothesis will exploit how active infection downregulates a “footprint” in the surface CCR5 population, distinguishing which subsets have been engaged by HIV. We recently reported how innovative superresolution optical imaging methods reflect CI virus use of distinct antigenic CCR5 forms. The two specific aims of this project will employ similar approaches to generate an unprecedented view of T/F coreceptor usage and entry on primary cells (human monocytes, lymphocytes and CD4+ T cells). The definition of “T/F CCR5” usage will impact HIV prevention/treatment efforts by informing the development of more potent and selective CCR5-based interventions and by elucidating complementary aspects of Env structure/function that confer coreceptor selectivity and the T/F phenotype. Such features can be explored by molecular methods and translated to HIV vaccine design.

抽象的 HIV 以病毒群的形式自然传播，仅通过一个或几个传播者/创始人建立感染 (T/F) 病毒的一些观察结果强烈表明，T/F 病毒是非随机地有利于生产的。通过共享签名基因型和表型特征传播当前关于环境的知识。共受体相互作用提出了解释所有 T/F 病毒包膜的创新概念。亚型优先使用 CCR5 辅助受体进入体外和体内，但细胞表面 CCR5 表达。多种功能和抗原形式，对抗逆转录病毒 CCR5 拮抗剂具有不同的敏感性 maraviroc (MVC)；对天然趋化因子配体的亲和力，和/或与抗 CCR5 单克隆抗体的反应性此外，各种抗 CCR5 mAb 抑制 CCR5 与标记的可溶性物质相互作用的能力。 gp120 或假病毒根据病毒株和目标细胞类型的不同而有所不同，这些发现共同提示了这一点。该探索性项目的中心假设：作为一个类别，T/F 病毒利用特征 CCR5 亚群可能有利于更有效的进入和病毒复制。对该假设的测试将利用活跃程度。感染下调表面 CCR5 群体中的“足迹”，区分哪些子集已被感染我们最近报道了创新的超分辨率光学成像方法如何反映 CI 病毒。该项目的两个具体目标将采用类似的方法来使用不同的抗原 CCR5 形式。生成 T/F 辅助受体使用和进入原代细胞（人单核细胞、淋巴细胞和 CD4+ T 细胞）“T/F CCR5”使用的定义将影响 HIV 预防/治疗工作。通过告知开发更有效和选择性的基于 CCR5 的干预措施并阐明 Env 结构/功能的互补方面赋予辅助受体选择性和 T/F 表型。可以通过分子方法探索特征并将其转化为艾滋病毒疫苗设计。