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

摘要 感染多年后，一小部分艾滋病毒携带者可以产生广泛的中和抗体。 (BNAbs)，定义为中和一系列不同艾滋病毒分离株的抗体。虽然诱导bNAbs是一个中心 作为HIV-1疫苗研究的焦点，bNAbs可能作为长效生物抗逆转录病毒治疗具有额外的作用 或者在病毒根除研究中作为免疫效应器。 广谱中和抗体针对HIV-1包膜糖蛋白，即表面gp120的异源三聚体 和跨膜gp41分子，质量分数为50%的多糖。猪瘟病毒抗体基因的克隆 HIV携带者发现了新的bNAb，其中和效力和广度不断增加 作为HIV-1治疗的临床研究。然而，单次注射bNAbs可以降低人的血浆病毒载量 对于HIV，对个体bNab产生抗药性的病毒变种迅速出现，限制了活性和治疗 BNab单一疗法的潜力。 传统上，抗体分子包含一个Fc区，与两个具有相同抗原的Fab区相连。 结合部位。最近，一种抗体被设计出来，它将三个不同的Fab区域结合成一个单一的 分子。SAR441236是一种三特异性bNab，结合了VRC01-LS、V1/V2的CD4bs特异性 与PGDM1400的糖链结合，以及与10E8v4的gp41MPER结合为一个抗体分子。 ACTG A5377是SAR441236的I期首次人体研究，研究SAR441236的安全性、药代动力学 (PK)，以及抗HIV-1活性。最多30名维勒姆参与者将被 研究采用单次输液剂量降级试验设计，随访24周。 这项提案的目标是利用A5377的样本来确定HIV-1是否在应对 “三重”生物艺术不同于传统的组合艺术，是为了确定病毒逃逸的机制 从一个三特异性的bNab。这项建议的目的是将创新的实验和数学相结合 用经典分子病毒学方法描述病毒血症的衰变并确定其机制 HIV-1从这种一流的三特异性bNab中逃脱。我们假设三特异性bNab，SAR441236， 清除血液中的无细胞和细胞相关病毒，在HIV-1中诱导大规模和动态的群体转移 Env准种，并在蛋白质和多糖水平上选择病毒逃逸变异体，以保持病毒的感染性 BNab的存在。这项建议的具体目的是确定SAR441236诱导的艾滋病毒的动力学- 1衰变，了解SAR441236对HIV-1包膜准种的影响，并定义HIV-1包膜和 葡聚糖可屏蔽SAR441236抗性的决定因素。我们的方法测试的是对 了解HIV-1在三特异性bNab选择压力下的动态和进化。

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.