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.

摘要 HIV作为病毒群自然传播，仅通过一个或几个传播/创始人建立感染 （T/F）病毒。几个观察结果强烈表明，T/F病毒是非随机的生产优势， 通过共享签名基因型和表型特征传播。目前关于环境的知识- 辅助受体的相互作用提出了创新的概念来解释T/F表型。所有T/F病毒包膜 亚型在体外和体内优先使用CCR 5辅助受体进入。然而，细胞表面CCR 5表达为 对抗逆转录病毒CCR 5拮抗剂具有不同敏感性的多种功能和抗原形式 马拉韦罗（MVC）;对天然趋化因子配体的亲和力和/或与抗CCR 5单克隆抗体的反应性 （mAb）。此外，各种抗CCR 5 mAb抑制CCR 5与标记的可溶性CCR 5相互作用的能力被证实。 GP 120或假病毒根据病毒株和靶细胞类型而变化。总的来说，这些发现促使 该探索性项目的中心假设：作为一类，T/F病毒利用签名CCR 5亚群 这可能有利于更有效的进入和病毒复制。对这一假设的检验将利用 感染下调了表面CCR 5群体中的“足迹”，区分了哪些子集已经被感染。 被艾滋病毒感染。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 使用不同的抗原CCR 5形式。该项目的两个具体目标将采用类似的方法， 产生了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CD 4 + T细胞）。“T/F CCR 5”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CCR 5的干预措施，并通过阐明 Env结构/功能的互补方面赋予共受体选择性和T/F表型。等 这些特征可以通过分子方法进行探索，并转化为HIV疫苗设计。