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.

项目摘要 Art Initiative（ARTI）是一个独特的临床关头 可能的通量和治疗艾滋病毒（PLWH）的大部分组成部分是可能的。在两个临床前 研究和最新的临床试验，ARTI的广泛中和抗体（BNAB）的输注显示令人兴奋 初步结果，但有关作用机制，必要的BNAB属性和 临床影响的程度仍然存在。此外，目前尚不清楚这些好处是否可以扩展到3500万 PLWH目前使用抑制性艺术，通过治疗中断和ART重新生效后使用BNAB。一些 计划或正在进行临床试验，但是人类研究的复杂性限制了明确阐明的能力 关键机制。我们的科学前提是，我们的分子定义，混合的BNAB敏感和抗性， 条形码传输/创始人（TF）SHIV/NHP模型系统被毒死，以确定程度和 bnab活性在人工/重新定局时的耐用性，并破译神经化效力的机械作用和 效应子功能对储层动力学，耐用的免疫反应和病毒控制。我们的小组有 产生了一系列工作，证明TF SHIV会再现HIV-1免疫发病发生的关键特征。 我们已经扩展了该模型，以结合遗传条形码和病毒接种物，含有定义的混合物 BNAB敏感和抗性病毒。在此系统中，每只动物都被TF SHIV的精确比率感染 编码具有相似的野生型（wt; wt; bnab敏感）和逃生突变体（em; bnab抗性）病毒 复制动力学，但对V3-Glycan BNAB的敏感性显着不同。因为WT和EM病毒具有 独特的条形码，我们可以随时间和整个组织跟踪BNAB敏感性与抗性病毒clonotypes 高通量测序，允许在统计上强大的动物内比较，以及 在治疗臂上进行比较。在这里，我们将利用这种新颖的NHP系统来确定 在Arti上进行的BNAB并重新定型并剖析BNABS中和和效应子功能的作用 比较4个治疗组的协调NHP实验：（i）单独使用ART，（ii）ART + BNAB，（iii）ART + BNAB 具有残疾效应子功能，（IV）ART + BNAB具有增强的效应子功能。然后，我们将确定是否 通过使用BNAB在动物的艺术重新生产中，可以看到类似的效果 接受了ATI。这种策略使我们能够定义BNAB的临床影响，并检验我们的整体假设， BNAB在ARTI上的中和效力和效应子功能对于在储层上的活动至关重要， 宿主免疫和诱导病毒控制。成功完成该项目将有实质性的 对HIV治疗领域的意义，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发展。