Determining the effects of broadly neutralizing antibodies at antiretroviral therapy initiation

确定广泛中和抗体在抗逆转录病毒治疗开始时的作用

• 批准号: 10772448
• 负责人: Katharine June Bar
• 金额: $ 88.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10772448
• 关键词: Acceleration; Aftercare; Animals; Antibodies; Antibody Response; Antibody Therapy; Autologous; Bar Codes; Binding; Biological Assay; Biological Models; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Trials; Disabled Persons; Escape Mutant; Genetic; Growth; HIV; HIV-1; High-Throughput Nucleotide Sequencing; Human; Immune response; Immunity; Infusion procedures; Interruption; Kinetics; Measurable; Measures; Methods; Modeling; Molecular; Pathogenesis; Persons; Plasma; Polysaccharides; Property; Research; Resistance; Role; System; T cell response; Testing; Time; Tissues; Viral; Viral reservoir; Virus; Virus Activation; Virus Replication; Work; antiretroviral therapy; clinical development; experimental study; immunoregulation; neutralizing antibody; nonhuman primate; novel; preclinical study; response; simian human immunodeficiency virus; transmission process; treatment arm; treatment group; trial planning; viral rebound

Project Summary ART initiation (ARTi) is a unique clinical juncture in which virus replication and host immune responses are in flux and treatment of a substantial component of people living with HIV (PLWH) is possible. In both preclinical studies and recent clinical trials, infusion of broadly neutralizing antibodies (bnAbs) at ARTi has shown exciting preliminary results, but key questions about the mechanisms of action, the requisite bnAb properties, and the extent of clinical impact remain. Further, it is unclear if these benefits can be extended to the >35 million PLWH currently on suppressive ART, by using bnAbs after treatment interruption and ART re-initiation. Several clinical trials are planned or ongoing, but the complexity of human research limit the ability to definitively elucidate key mechanisms. Our scientific premise is that our molecularly defined, mixed bnAb-sensitive and resistant, barcoded transmitted/founder (TF) SHIV/NHP model system is uniquely poised to determine the extent and durability of bnAb activity at ARTi/re-initiation and decipher the mechanistic role of neutralization potency and effector function on reservoir dynamics, durable immune responses, and virus control. Our group has generated a body of work demonstrating that TF SHIVs reproduce key features of HIV-1 immunopathogenesis. We have expanded the model to incorporate genetic barcoding and virus inocula containing defined mixtures of bnAb-sensitive and resistant viruses. In this system, each animal is infected with a precise ratio of TF SHIVs encoding wildtype (WT; bnAb-sensitive) and escape mutant (EM; bnAb resistant) viruses, which have similar replication kinetics but markedly different sensitivities to V3-glycan bnAbs. Because WT and EM viruses have unique barcodes, we can track bnAb-sensitive vs. resistant virus clonotypes over time and across tissues through high-throughput sequencing, allowing for statistically powerful within-animal comparisons, as well as comparisons across treatment arms. Here, we will leverage this novel NHP system to determine the effects of bnAbs at ARTi and re-initiation and dissect the roles of bnAbs’ neutralizing and effector functions through a coordinated NHP experiment comparing 4 treatment groups: (i) ART alone, (ii) ART + bnAb, (iii) ART + bnAb with disabled effector function, and (iv) ART + bnAb with enhanced effector function. We will then determine if similar effects can be seen with use of bnAbs at ART re-initiation in animals already on suppressive ART who underwent ATI. This strategy allows us to define bnAb’s clinical impact and test our overall hypothesis that both the neutralizing potency and effector function of bnAbs at ARTi are essential to activity on the reservoir, host immunity, and induction of virus control. Successful completion of this project would have substantial significance to the HIV cure field, as it rigorously tests promising roles for bnAbs in HIV cure strategies that could guide the clinical development of bnAbs in cure strategies.

项目概要 ART 启动 (ARTi) 是一个独特的临床关口，其中病毒复制和宿主免疫反应处于 在临床前阶段，大部分艾滋病毒感染者（PLWH）的流动和治疗都是可能的。 研究和最近的临床试验表明，在 ARTi 中输注广泛中和抗体 (bnAbs) 的结果令人兴奋 初步结果，但关于作用机制、必要的 bnAb 特性和 此外，尚不清楚这些益处是否可以扩大到超过 3500 万。 PLWH 目前正在接受抑制性 ART，在治疗中断和重新开始 ART 后使用 bnAb。 临床试验已计划或正在进行，但人类研究的复杂性限制了明确阐明的能力 我们的科学前提是我们的分子定义、混合 bnAb 敏感和耐药、 带条形码的传播/创始人 (TF) SHIV/NHP 模型系统具有独特的优势，可以确定范围和 ARTi/重新启动时 bnAb 活性的持久性，并破译中和效力的机制作用和 我们的研究小组拥有对病毒库动态、持久免疫反应和病毒控制的效应功能。 开展了大量工作，证明 TF SHIV 重现了 HIV-1 免疫发病机制的关键特征。 我们扩展了该模型，以纳入遗传条形码和包含特定混合物的病毒接种物 bnAb 敏感和耐药病毒在该系统中，每只动物都感染了精确比例的 TF SHIV。 编码野生型（WT；bnAb 敏感）和逃逸突变体（EM；bnAb 抗性）病毒，它们具有相似的特性 复制动力学，但对 V3-聚糖 bnAb 的敏感性明显不同，因为 WT 和 EM 病毒具有。 独特的条形码，我们可以随着时间的推移和跨组织跟踪 bnAb 敏感与耐药的病毒克隆型 高通量测序，允许极其强大的动物内比较，以及 在这里，我们将利用这种新颖的 NHP 系统来确定治疗组的效果。 BNAb 在 ARTi 上的作用，并通过以下方法重新启动和剖析 bnAb 的中和功能和效应功能的作用： 协调 NHP 实验比较 4 个治疗组：(i) 单独 ART，(ii) ART + bnAb，(iii) ART + bnAb 具有禁用的效应器功能，以及（iv）具有增强的效应器功能的 ART + bnAb 然后我们将确定是否。 在已经接受抑制性 ART 的动物中，在重新开始 ART 时使用 bnAb 可以看到类似的效果 实施 ATI 使我们能够定义 bnAb 的临床影响并测试我们的总体假设： ARTi 上 bnAb 的中和效力和效应器功能对于储存库的活性至关重要， 宿主免疫和诱导病毒控制将具有重大意义。 对 HIV 治疗领域具有重要意义，因为它严格测试了 bnAb 在 HIV 治疗策略中的有希望的作用， 可以指导 bnAb 在治疗策略中的临床开发。