Broadly neutralizing antibody combinations with single virions in HIV+ plasma

HIV血浆中单一病毒粒子的广泛中和抗体组合

基本信息

  • 批准号:
    10655874
  • 负责人:
  • 金额:
    $ 38.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-18 至 2023-01-22
  • 项目状态:
    已结题

项目摘要

Recently discovered broadly HIV-neutralizing antibodies (bnAbs) are being actively investigated for HIV/AIDS treatment, functional cure and/or prevention. A variety of such bnAbs are known and classified according to their epitopes clusters on the HIV envelope (Env). Rigorous preclinical studies evince potential advantages of engineered bnAbs over currently used antiretroviral drugs (ARVs); including infrequent administration, lower risk of side effects and genotoxicity, capacity to target latent HIV reservoirs, promotion of host antiviral immune responses, and insensitivity to conventional ARV resistance. Currently, the major obstacle for realizing the clinical potential of single bnAbs is that all of them exhibit limits in covering epitope variability, which allows virus escape. One logical mitigation strategy is to utilize combinations of three bnAbs, each targeting a distinct epitope cluster. Combinations that promote extensive concurrent binding of bnAbs to the same targets (virions or trimers) in plasma virus populations are expected to be especially escape resistant. Yet whether and how this goal can be obtained for HIV prevention or therapy remains unclear. Conventional neutralization assays do not directly measure bnAb-virion binding but have shown that combining bnAb classes improves breadth and potency. Models predict that bnAb class combinations can act collectively on a single virus strain. However, clinical trials suggest a more complex picture. Several trials have tested combined bnAbs, but sustained suppression of viremia has not yet been demonstrated. Collectively, these findings introduce several important questions regarding concurrent bnAb binding in vivo: Are certain bnAb class combinations distinguishable as “superior” in establishing concurrent virion/trimer binding within major fractions of plasma virus swarms? How consistently does such desirable coverage occur across individuals and subtypes? Does HIV+ human plasma contain immunoreactive particles (exosomes, immature virions); circulating anti-Env antibodies or other factors that perturb desirable concurrent binding patterns? Goal of the project is to answer these questions by direct analyses of bnAb-virion interactions in native plasma. Our hypothesis is that this unique endeavor can be accomplished by novel quantitative single molecule and fluorescence correlation spectroscopy (FCS) detection methods applied to plasma virions in situ. Two Specific Aims are: Aim 1. Establish the immunoreactivity patterns of bnAb combinations against single virions or envelope trimers; Aim 2. Characterize interactions of bnAbs and bnAb combinations with single virions in HIV+ plasma. Project output will be an unprecedented tier of data informing the nature of combined bnAb action in vivo and prospects for triple bnAb combinations to counter HIV escape. Our data will uniquely define principles, limits, and opportunities in using bnAb combinations to target circulating virions in the HIV+ human population. This knowledge should impact the selection of bnAb class combinations for future clinical testing and inform the outcomes of past and ongoing clinical trials. Further, the qualitative and quantitative data from this project will inform the feasibility of developing patient-specific bnAb class cocktails.
最近发现的广泛HIV中和抗体(bnAbs)正在积极研究HIV/AIDS 治疗、功能性治愈和/或预防。多种这样的bnAb是已知的,并根据它们的生物学特性进行分类。 HIV包膜上的表位簇(Env)。严格的临床前研究表明, 工程化bnAb优于目前使用的抗逆转录病毒药物(ARV);包括不频繁给药,风险较低 副作用和遗传毒性,靶向潜伏的HIV宿主的能力,促进宿主的抗病毒免疫 对常规抗逆转录病毒药物耐药性不敏感。目前,实现这一目标的主要障碍是, 单一bnAb的临床潜力在于它们都在覆盖表位可变性方面表现出限制,这使得病毒 逃跑一种合乎逻辑的缓解策略是利用三种bnAb的组合,每种bnAb靶向不同的表位 集群促进bnAb与相同靶标(病毒体或三聚体)广泛同时结合的组合 在血浆中,预期病毒群体特别具有逃逸抗性。然而,这一目标是否以及如何能够 用于艾滋病毒预防或治疗的药物仍不清楚。常规的中和试验不直接 测量bnAb-病毒体结合,但已经显示组合bnAb类别提高了广度和效力。 模型预测bnAb类组合可以共同作用于单个病毒株。然而,临床试验 暗示了一个更复杂的画面。几项试验已经测试了组合的bnAb,但是持续抑制了BnAb的表达。 病毒血症尚未得到证实。总的来说,这些发现提出了几个重要的问题 关于体内同时bnAb结合:某些bnAb类别组合是否可区分为“上级”, 在血浆病毒群的主要部分中建立同时的病毒体/三聚体结合?如何一致 这种理想的覆盖范围是否在个人和亚型之间出现?HIV+人血浆是否含有 免疫反应性颗粒(外来体、未成熟病毒体);循环抗Env抗体或其他因子, 扰乱理想的并发绑定模式?该项目的目标是通过直接分析来回答这些问题 bnAb-病毒体相互作用的研究。我们的假设是,这种独特的奋进可以完成 通过新颖的定量单分子和荧光相关光谱(FCS)检测方法 应用于原位血浆病毒体。两个具体目标是:目标1。建立bnAb的免疫反应性模式 针对单一病毒体或包膜三聚体的组合; Aim 2.表征bnAb和bnAb的相互作用 与HIV+血浆中的单个病毒体组合。项目产出将是一个前所未有的数据层, 组合bnAb在体内作用的性质和三重bnAb组合对抗HIV逃逸的前景。 我们的数据将独特地定义使用bnAb组合靶向循环的原则、限制和机会。 HIV+人群中的病毒体。这一知识应影响bnAb类别组合的选择 用于未来的临床试验,并告知过去和正在进行的临床试验的结果。此外,定性和 来自该项目的定量数据将告知开发患者特异性bnAb类鸡尾酒的可行性。

项目成果

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Krishanu Ray其他文献

Krishanu Ray的其他文献

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{{ truncateString('Krishanu Ray', 18)}}的其他基金

Broadly neutralizing antibody combinations with single virions in HIV+ plasma
HIV血浆中单一病毒粒子的广泛中和抗体组合
  • 批准号:
    10699469
  • 财政年份:
    2023
  • 资助金额:
    $ 38.63万
  • 项目类别:
Conformational Dynamics of HIV Envelope by Single Molecule Spectroscopy
单分子光谱研究 HIV 包膜的构象动力学
  • 批准号:
    8947352
  • 财政年份:
    2015
  • 资助金额:
    $ 38.63万
  • 项目类别:
Conformational Dynamics of HIV Envelope by Single Molecule Spectroscopy
单分子光谱研究 HIV 包膜的构象动力学
  • 批准号:
    9340245
  • 财政年份:
    2015
  • 资助金额:
    $ 38.63万
  • 项目类别:
Conformational Dynamics of HIV Envelope by Single Molecule Spectroscopy
单分子光谱研究 HIV 包膜的构象动力学
  • 批准号:
    9148226
  • 财政年份:
    2015
  • 资助金额:
    $ 38.63万
  • 项目类别:
Single Molecule Studies of HIV Envelope Properties
HIV 包膜特性的单分子研究
  • 批准号:
    8416423
  • 财政年份:
    2011
  • 资助金额:
    $ 38.63万
  • 项目类别:
Single Molecule Studies of HIV Envelope Properties
HIV 包膜特性的单分子研究
  • 批准号:
    8140932
  • 财政年份:
    2011
  • 资助金额:
    $ 38.63万
  • 项目类别:
Single Molecule Studies of HIV Envelope Properties
HIV 包膜特性的单分子研究
  • 批准号:
    8232033
  • 财政年份:
    2011
  • 资助金额:
    $ 38.63万
  • 项目类别:
Single Molecule Studies of HIV Envelope Properties
HIV 包膜特性的单分子研究
  • 批准号:
    8607884
  • 财政年份:
    2011
  • 资助金额:
    $ 38.63万
  • 项目类别:
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