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: 10655874
• 负责人: Krishanu Ray
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10655874
• 关键词: AIDS prevention; AIDS/HIV problem; Address; Anti-Retroviral Agents; Antibodies; Antiretroviral drug resistance; Binding; Binding Sites; Biological Assay; Clinical; Clinical Trials; Complex; Data; Detection; Development; Drug Kinetics; Engineering; Epitopes; Evolution; Exhibits; Fluorescence; Fluorescence Resonance Energy Transfer; Future; Goals; HIV; HIV Infections; HIV therapy; Human; Immune response; In Situ; In Vitro; Individual; Infection; Interruption; Knowledge; Mannose; Measures; Mediating; Methods; Nature; Outcome; Output; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Population; Prevention; Prevention therapy; Primary Infection; Process; Resistance; Risk; Sampling; Specificity; Spectrum Analysis; Testing; Variant; Viral; Viremia; Virion; Virus; antibody engineering; detection method; exosome; experience; experimental study; genotoxicity; immunoreactivity; improved; in vivo; latent HIV reservoir; neutralizing antibody; novel; particle; preclinical study; predictive modeling; prevent; research clinical testing; side effect; single molecule; viral rebound

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.

最近发现的广泛的HIV中和抗体（BNAB）正在积极研究HIV/AIDS 治疗，功能治愈和/或预防。各种此类bnab是根据他们的 艾滋病毒信封（Env）上的表位簇。严格的临床前研究证明了潜在的优势 当前使用的抗逆转录病毒药物（ARV）的工程BNAB；包括频繁的管理，降低风险 副作用和遗传毒性，靶向潜在艾滋病毒库的能力，促进宿主抗病毒免疫 对常规ARV抗性的反应和不敏感。目前，实现的主要障碍 单个BNAB的临床潜力是，它们都显示出覆盖表位变异性的限制，这允许病毒 逃脱。一种逻辑缓解策略是利用三个BNAB的组合，每个BNAB的靶向不同 簇。促进BNABS与相同靶标（视觉或三聚体）的广泛并发结合的组合 在血浆病毒中，预计尤其是抗逃生性的。然而，这个目标是否以及如何 可用于预防HIV或治疗尚不清楚。常规神经化测定不会直接 测量BNAB视觉结合，但表明将BNAB类组合提高了宽度和效力。 模型预测BNAB类组合可以集体作用于单个病毒菌株。但是，临床试验 提出更复杂的图片。几项试验已经测试了BNAB的组合，但持续抑制 病毒血症尚未得到证明。这些发现共同介绍了几个重要问题 关于并发的BNAB结合体内：某些BNAB类组合是否可以区分为“优越” 在血浆病毒群的主要部分内建立并发的病毒/三聚体结合？多么一致 这种理想的覆盖范围是否发生在个人和亚型之间？艾滋病毒+人血浆是否包含 免疫反应性颗粒（外泌体，未成熟病毒）；循环抗ENV抗体或其他因素 烧伤期望的并发结合模式？该项目的目标是通过直接分析回答这些问题 天然等离子体中的BNAB视觉相互作用。我们的假设是可以实现这一独特的努力 通过新型的定量单分子和荧光相关光谱（FCS）检测方法 原位应用于血浆病毒。两个具体的目的是：目标1。建立BNAB的免疫反应性模式 针对单个病毒或信封三聚体的组合； AIM 2。表征BNAB和BNAB的相互作用 HIV+等离子体中与单个病毒的组合。项目输出将是前所未有的数据通知 BNAB作用在体内的合并性质和三杆BNAB组合的前景来对抗HIV逃脱。 我们的数据将独特地定义使用BNAB组合来循环的原理，限制和机会 艾滋病毒+人口中的病毒。这些知识应影响BNAB类组合的选择 用于将来的临床测试，并为过去和正在进行的临床试验的结果提供信息。此外，定性和 来自该项目的定量数据将为开发患者特异性BNAB类鸡尾酒的可行性提供信息。