HIV-1 dynamics and evolution during trispecific broadly neutralizing antibody therapy

摘要 经过多年的感染，一小部分艾滋病毒感染者可以产生广泛的中和抗体 （bnAbs），定义为中和多种HIV分离株的抗体。虽然引出bnAb是一个核心问题， 作为HIV-1疫苗研究的重点，bnAbs可能作为长效生物抗逆转录病毒疗法发挥额外作用 或作为病毒根除研究中的免疫效应臂。 广泛中和抗体靶向HIV-1包膜糖蛋白，表面gp 120的异源三聚体 和跨膜gp 41分子，其为50质量%的聚糖。克隆抗体基因， HIV感染者发现了新的bnAb，其中和效力和宽度不断增加， 作为HIV-1治疗的临床研究。而单次输注bnAb可以降低人的血浆病毒载量， 对于HIV，对单个bnAb具有抗性的病毒变体迅速出现，并限制了其活性和治疗效果。 bnAb单药治疗的潜力。 典型地，抗体分子含有连接到具有相同抗原的两个Fab区的Fc区 结合位点。最近，一种抗体被工程化，其将三个不同的Fab区组合成单个Fab区。 分子。SAR 441236是一种三特异性bnAb，结合了VRC 01-LS的CD 4 bs特异性、V1/V2特异性和V3特异性。 PGDM 1400的聚糖定向结合和10 E8 v4的gp 41 MPER结合成一个抗体分子。 ACTG A5377是SAR 441236的I期首次人体研究，旨在研究其安全性、药代动力学 (PK)和抗HIV-1活性。最多30名病毒血症受试者将接受 在单次输注剂量递减试验设计中进行研究，随访24周。 该提案的目标是利用来自A5377的样本来确定HIV-1是否会因 “三联”生物ART不同于传统的联合ART，并确定病毒逃逸的机制 来自三特异性bnAb这个建议的目的是将联合收割机创新的实验和数学 用经典的分子病毒学方法来描述病毒血症的衰变，并确定 HIV-1从这种一流的三特异性bnAb中逃逸。我们假设三特异性bnAb，SAR 441236， 清除血液中的无细胞和细胞相关病毒，诱导HIV-1中大量动态的群体转移， env准种，并在蛋白质和聚糖水平上选择病毒逃逸变体，以维持 bnAb的存在。本提案的具体目的是确定SAR 441236诱导的HIV-1的动力学。 1衰变，了解SAR 441236对HIV-1 env准种的影响，并定义HIV-1 env和 SAR 441236耐药性的聚糖屏蔽决定因素。我们的方法测试的假设是核心， 了解HIV-1在三特异性bnAb选择压力下的动力学和进化。

Abstract After years of infection, a small subset of people with HIV can develop broadly neutralizing antibodies (bnAbs), defined as antibodies that neutralize a diverse range of HIV isolates. While eliciting bnAbs is a central focus of HIV-1 vaccine research, bnAbs may have additional roles as long-acting biologic antiretroviral therapy or as an immune effector arm in virus eradication studies. Broadly neutralizing antibodies target the HIV-1 envelope glycoproteins, heterotrimers of surface gp120 and transmembrane gp41 molecules, that are 50% glycan by mass. The cloning of antibody genes from individuals with HIV identified new bnAbs with increasing potency and breadth of neutralization that have been studied clinically as HIV-1 treatment. Whereas single infusions of bnAbs can reduce plasma virus loads in people with HIV, virus variants resistant to the individual bnAb emerge quickly and limit the activity and therapeutic potential of bnAb monotherapy. Classically, an antibody molecule contains an Fc region linked to two Fab regions with identical antigen binding sites. Recently, an antibody was engineered that combined three distinct Fab regions into a single molecule. SAR441236 is a tri-specific bnAb that combines the CD4bs specificity of VRC01-LS, the V1/V2 glycan-directed binding of PGDM1400, and the gp41 MPER binding of 10E8v4 into one antibody molecule. ACTG A5377 is a phase I first-in-human study of SAR441236 that investigates the safety, pharmacokinetics (PK), and anti-HIV-1 activity of this novel trispecific bnAb. A maximum of thirty viremic participants will be studied in a single infusion dose de-escalation trial design with 24 weeks of follow-up. The goal of this proposal is to leverage samples from A5377 to determine if HIV-1 decay in response to “triple” biologic ART differs from conventional combination ART and to define the mechanisms of virus escape from a trispecific bnAb. The purpose of this proposal is to combine innovative experimental and mathematical approaches with classic molecular virology to characterize the decay of viremia and define the mechanisms of HIV-1 escape from this first-in-class trispecific bnAb. We hypothesize that the trispecific bnAb, SAR441236, clears cell-free and cell-associated virus from blood, induces large and dynamic population shifts in the HIV-1 env quasispecies, and selects for virus escape variants at the protein and glycan level to maintain infectivity in the presence of bnAb. Specific Aims of this proposal are to determine the kinetics of SAR441236-induced HIV- 1 decay, understand the effects of SAR441236 on HIV-1 env quasispecies, and define the HIV-1 env and glycan shield determinants of SAR441236 resistance. Our approaches test hypotheses that are central to understand the dynamics and evolution of HIV-1 under a trispecific bnAb selection pressure.