Defining the mechanisms of HIV resistance to bNAbs in humans

定义人类 HIV 对 bNAb 的耐药机制

• 批准号: 10446159
• 负责人: Marina Caskey
• 金额: $ 156.98万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446159
• 关键词: AIDS prevention; Animal Model; Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody Therapy; Autologous; Cell Culture Techniques; Cell Separation; Cells; Clinical; Clinical Research; Clinical Trials; Complex; Computer Models; Disease remission; Dose; Elements; Epitopes; Evolution; Exhibits; Genetic; Goals; HIV; HIV resistance; HIV-1; Human; Immune response; Immune system; In Vitro; Incidence; Individual; Infection; Infection prevention; Interruption; Lead; Libraries; Machine Learning; Maps; Masks; Mediating; Methods; Modality; Molecular; Molecular Conformation; Mutate; Mutation; Nature; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Polysaccharides; Population; Population Sizes; Preventive; Proteins; Protocols documentation; Proviruses; Resistance; Sampling; Serum; Site; Surface; Testing; Therapeutic; Therapeutic Intervention; V3 Loop; Variant; Viral; Viremia; Virus; antiretroviral therapy; base; clinical development; clinically relevant; deep sequencing; design; experience; experimental study; mutant; neutralizing antibody; next generation; novel; novel strategies; novel therapeutics; preclinical study; prevent; preventive intervention; resistance mutation; resistant strain; response; success; viral rebound; viral resistance

PROJECT SUMMARY Combination antiretroviral therapy (ART) revolutionized the treatment and prevention of HIV-1 infection. However, ART does not eradicate established infection and worldwide HIV-1 incidence rates remain high and have been declining slowly. Thus, the search for novel preventive and therapeutic interventions remains a high priority. In recent years, broadly neutralizing antibodies (bNAbs) emerged as a long-acting alternative to daily ART and as a promising strategy to achieve long-term treatment-free HIV-1 control. bNAbs differ from ART in that they engage the host immune system by virtue of their Fc effector domains and therefore have the potential to mediate killing of infected cells and modulate or enhance HIV-specific immune responses. However, bNAbs are vulnerable to escape by HIV-1 variants. During HIV-1 infection, antibody responses co-evolve with a large population of rapidly mutating viruses, such that variants that are resistant to individual antibodies are frequently encountered. Consistent with this high level of diversity, several clinical studies have demonstrated that bNAb monotherapy leads to transient declines in viremia with rapid selection of bNAb-resistant viral strains. In contrast, a combination of two bNAbs targeting non-overlapping Env epitopes maintained viral suppression in participants harboring antibody sensitive viruses who had achieved viral suppression with ART and subsequently received repeated doses of bNAbs during ART interruption. These early studies demonstrate the potential therapeutic application of bNAbs but also highlight the need to better understand viral escape pathways leading to bNAb resistance. Although resistance to some bNAbs (i.e. anti-V3 loop) is predicated on known features of Env, the determinants of resistance are poorly defined for other bNAbs and for combinations of bNAbs. The overarching goals of this proposal are to understand the diversity of pathways leading to bNAb escape and use this information to guide the design of more effective optimized bNAb combinations that prevent emergence of resistant variants. This proposal has four interrelated aims directed at accomplishing these goals: (1) Determine the sequence elements that lead to viral resistance to bNAb administration in humans using newly developed next generation deep sequencing methods; (2) Systematically map all possible viable bNAb resistance mutations to identify mechanisms of escape across viral strains and subtypes by producing and testing complete libraries of Env mutants; (3) Determine the nature of clinically relevant bNAb-resistant HIV-1 variants that can be selected in cell culture in the presence or absence of autologous serum; (4) Develop computational models that define mechanisms of HIV-1 bNAb resistance by integrating the sequence information obtained from Aims 1-3.

项目概要 联合抗逆转录病毒疗法 (ART) 彻底改变了 HIV-1 感染的治疗和预防。 然而，ART 并不能根除已确定的感染，全球范围内的 HIV-1 发病率仍然很高， 一直在缓慢下降。因此，寻找新的预防和治疗干预措施仍然是一个紧迫的任务 优先事项。近年来，广泛中和抗体（bNAb）作为每日抗体的长效替代品出现。 ART 是实现长期免治疗 HIV-1 控制的有前途的策略。 bNAb 与 ART 的不同之处在于 它们凭借 Fc 效应域参与宿主免疫系统，因此具有潜在的潜力 介导杀死受感染细胞并调节或增强 HIV 特异性免疫反应。然而，bNAb 很容易被 HIV-1 变种逃脱。在 HIV-1 感染期间，抗体反应与大量抗体共同进化 快速突变的病毒群体，对单个抗体具有抗性的变体经常出现 遭遇。与这种高水平的多样性相一致，多项临床研究表明 bNAb 单一疗法可导致病毒血症短暂下降，并快速选择 bNAb 耐药病毒株。相比之下， 两种靶向非重叠 Env 表位的 bNAb 组合维持了参与者的病毒抑制 携带抗体敏感病毒，通过 ART 实现病毒抑制，随后接受 ART 中断期间重复服用 bNAb。这些早期研究证明了潜在的治疗作用 bNAb 的应用，但也强调需要更好地了解导致 bNAb 的病毒逃逸途径 反抗。尽管对某些 bNAb 的抗性（即抗 V3 环）是基于 Env 的已知特征，但 对于其他 bNAb 和 bNAb 组合，耐药性的决定因素尚不清楚。首要的 该提案的目标是了解导致 bNAb 逃逸的途径的多样性并利用该途径 指导设计更有效的优化 bNAb 组合的信息，以防止出现 抗性变种。该提案有四个相互关联的目标，旨在实现这些目标：(1) 确定 使用新开发的导致病毒对人类 bNAb 给药产生抗性的序列元件 下一代深度测序方法； (2) 系统地绘制所有可能的可行 bNAb 耐药突变图谱 通过生成和测试完整的文库来确定跨病毒株和亚型的逃逸机制 Env 突变体； (3) 确定可供选择的临床相关bNAb耐药HIV-1变异体的性质 在存在或不存在自体血清的细胞培养中； (4) 开发计算模型来定义 通过整合从目标 1-3 获得的序列信息来研究 HIV-1 bNAb 耐药机制。