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自然传播为病毒群，该病毒仅通过一个或几个传播/创始人建立感染（T/F）病毒。几种观察结果强烈表明T/F病毒对产品不受限制地受到青睐通过共享的特征基因型和表型特征传播。有关env-的当前知识共感受器相互作用提出了创新的概念来解释T/F表型。所有人的T/F病毒信封亚型优先使用CCR5共感染者在体外和体内进入。但是表达细胞表面CCR5 在多种功能和抗原形式中，对抗逆转录病毒CCR5拮抗剂具有不同的敏感性 Maroviroc（MVC）;天然趋化因子配体的亲和力和/或反应性与抗CCR5单克隆抗体的反应性（mabs）。此外，各种抗CCR5 mAb的能力可以抑制CCR5相互作用与两种标记的固体相互作用 GP120或假病毒根据病毒菌株和靶细胞类型而变化。总的来说，这些发现提示这个探索性项目的中心假设：作为类别，T/F病毒利用Signature CCR5亚群（S）这种潜在的有利于更有效的进入和病毒复制。该假设的检验将利用如何活跃感染下调表面CCR5人群中的“足迹”，区分了哪些子集已经由艾滋病毒参与。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产生对t/f coreceptor使用和对原代细胞的进入的前所未有的视图（人单核细胞，淋巴细胞和CD4+ T细胞）。 “ T/F CCR5”使用的定义将影响预防HIV/治疗工作通过告知开发更多潜在和选择性的基于CCR5的干预措施，并阐明 ENV结构/功能的互补方面，会议共感受器选择性和T/F表型。这样的可以通过分子方法探索特征，并转化为HIV疫苗设计。