Determining the effects of broadly neutralizing antibodies at antiretroviral therapy initiation

项目摘要 ARTI是病毒复制和宿主免疫反应的独特临床结合点。 很大一部分艾滋病毒携带者(PLWH)的传播和治疗是可能的。在两个临床前阶段 研究和最近的临床试验表明，在ARTI输注广谱中和抗体(BNAbs)是令人兴奋的 初步结果，但关键问题是作用机制，必要的bNab属性，以及 临床影响的程度仍然存在。此外，目前还不清楚这些福利能否扩大到3500万英镑。 PLWH目前正在进行抑制ART，在治疗中断和ART重新启动后使用bNAbs。几个 临床试验是计划中的或正在进行的，但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的，混合的bNab敏感和耐药， 条形码传输/方正(TF)SHIV/NHP模型系统是唯一可以确定范围和 在ARTI/重新启动时bNab活性的持久性并破译中和效价和 对水库动态、持久的免疫反应和病毒控制的效应器功能。我们的团队已经 产生了一系列工作，证明了TFSHIV复制了HIV-1免疫致病机制的关键特征。 我们已经扩展了模型，以包括遗传条形码和病毒接种，其中包含定义的混合 BNab敏感和抗性病毒。在这个系统中，每只动物都被感染了精确比例的tf shv。 编码野生型(WT；bNab敏感)和逃逸突变(EM；bNab抗性)病毒，这两种病毒具有类似的 复制动力学，但对V3-葡聚糖bNAbs的敏感性明显不同。因为WT和EM病毒有 独特的条形码，我们可以跟踪bNab敏感和耐药病毒克隆类型随着时间的推移和跨组织通过 高通量测序，允许进行统计上强大的动物内比较，以及 不同治疗手段的比较。在这里，我们将利用这一新颖的NHP系统来确定 BNAbs在ARTI和重新启动，并剖析bNAbs的中和作用和效应功能通过 比较4个治疗组的NHP协同实验：(I)单独应用ART，(Ii)ART+bNab，(Iii)ART+bNab 禁用效应器功能，以及(Iv)具有增强效应器功能的ART+bNab。然后我们将确定是否 在已经抑制ART的动物中使用bNAbs重新启动ART也可以看到类似的效果 接受了ATI治疗。这一策略允许我们定义bNab的临床影响，并测试我们的总体假设 在ARTi处的bNAbs的中和效力和效应器功能对于在储藏物上的活性是必不可少的， 宿主免疫和诱导病毒控制。这一项目的成功完成将对 对艾滋病毒治疗领域的意义，因为它严格测试了bNAbs在艾滋病毒治疗策略中有希望的作用， 可指导临床制定bNAbs的治疗策略。

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.