CCR5 determinants for the HIV transmitted founder phenotype

HIV 传播创始人表型的 CCR5 决定因素

• 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
• 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

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。一些观察结果强烈表明，T/F 病毒非随机地有利于生产 通过共享签名基因型和表型特征进行传播。目前有关Env-的知识 共受体相互作用提出了解释 T/F 表型的创新概念。所有T/F病毒包膜 亚型优先使用 CCR5 辅助受体进入体外和体内。然而细胞表面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 马拉维罗（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 （单克隆抗体）。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靶细胞类型而变化。总的来说，这些发现提示 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 这可能有利于更有效的进入和病毒复制。对该假设的检验将利用如何活跃 感染下调表面 CCR5 群体中的“足迹”，区分哪些子集已被感染 感染艾滋病毒。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 使用不同的抗原CCR5形式。该项目的两个具体目标将采用类似的方法 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”使用的定义将影响艾滋病毒预防/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。这样的 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。