Determining the effects of broadly neutralizing antibodies at antiretroviral therapy initiation

项目摘要 ART启动（阿尔蒂）是一个独特的临床接合点，其中病毒复制和宿主免疫应答处于同步状态。 艾滋病毒感染者（PLWH）的很大一部分的流动和治疗是可能的。在两种临床前 研究和最近的临床试验显示，在阿尔蒂输注广泛中和抗体（bnAb）令人兴奋， 初步结果，但关键问题的作用机制，必要的bnAb的性质， 临床影响的程度仍然存在。此外，目前还不清楚这些好处是否可以扩大到> 3500万 PLWH目前正在接受抑制性ART，在治疗中断和ART重新开始后使用bnAb。几 临床试验正在计划或进行中，但人体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bnAb敏感和耐药， 条形码传输/创始人（TF）SHIV/NHP模型系统是唯一准备确定的程度， 在阿尔蒂/重新启动时bnAb活性的持久性，并解释中和效力的机制作用， 效应子对水库动态、持久免疫应答和病毒控制的作用。我们集团 产生了大量的工作，证明TF SHIV复制了HIV-1免疫发病机制的关键特征。 我们已经扩展了该模型，以纳入遗传条形码和含有定义的混合物的病毒接种物， bnAb敏感和耐药病毒。在这个系统中，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，其具有类似的 复制动力学，但对V3-聚糖bnAb的敏感性显著不同。因为WT和EM病毒 独特的条形码，我们可以跟踪bnAb敏感与耐药病毒克隆型随着时间的推移和跨组织，通过 高通量测序，允许统计学上强大的动物内比较，以及 治疗组之间的比较。在这里，我们将利用这种新的NHP系统来确定 bnAbs在阿尔蒂和重新启动中的作用，并通过一个 比较4个治疗组的协调NHP实验：（i）单独ART，（ii）ART + bnAb，（iii）ART + bnAb 具有失能的效应子功能的ART + bnAb，和（iv）具有增强的效应子功能的ART + bnAb。然后我们将确定， 在已经进行抑制性ART的动物中，在ART重新开始时使用bnAb可以看到类似的效果， 接受ATI。这一策略使我们能够确定bnAb的临床影响，并测试我们的总体假设， bnAb在阿尔蒂上的中和效力和效应子功能对于在储库上的活性是必需的， 宿主免疫和诱导病毒控制。成功完成这一项目将产生重大影响。 它对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bnAbs治疗策略的临床开发。

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.