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.

项目摘要 抗逆转录病毒疗法（ART）彻底改变了HIV-1感染的治疗和预防。 但是，艺术并未消除已建立的感染，全球HIV-1发病率仍然很高，并且 一直在慢慢下降。因此，寻找新颖的预防和治疗干预措施仍然很高 优先事项。近年来，广泛中和抗体（BNAB）是每日的长效替代品 艺术和作为实现长期无治疗HIV-1控制的有前途的策略。 bnabs与艺术不同 他们凭借其FC效应子领域参与宿主免疫系统，因此具有潜力 介导杀死感染细胞并调节或增强HIV特异性免疫反应。但是，bnabs HIV-1变体很容易逃脱。在HIV-1感染期间，抗体反应与大型 迅速突变病毒的种群，使得对单个抗体具有抗性的变体经常是 遭遇。与这种高度多样性一致，一些临床研究表明BNAB 单一疗法导致病毒血症的短暂下降，并快速选择抗BNAB的病毒菌株。相比之下， 靶向非重叠的ENV表位的两个BNAB的组合在参与者中保持病毒抑制 携带抗体敏感病毒，通过ART实现病毒抑制并随后接受 在艺术中​​断期间，反复剂量的bnabs。这些早期研究证明了潜在的治疗 BNABS的应用，但也强调需要更好地了解导致BNAB的病毒逃生途径 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 抗性的决定因素对于其他BNAB和BNAB的组合的定义很差。总体 该提议的目标是了解导致BNAB逃脱的途径的多样性并使用 指导设计更有效优化的BNAB组合的信息，以防止出现 抗性变体。该提案具有四个相互关联的目标，旨在实现这些目标：（1）确定 使用新发展 下一代深度测序方法； （2）系统地绘制所有可能的可行BNAB抗性突变 通过生成和测试完整的库来确定跨病毒菌株和亚型的逃生机制 env突变体； （3）确定可以选择的临床相关抗BNAB抗HIV-1变体的性质 在存在或不存在自体血清的细胞培养中； （4）开发定义的计算模型 通过整合从AIMS 1-3获得的序列信息，HIV-1 BNAB抗性的机理。