Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1

补充广泛中和抗体和自体反应，以限制病毒逃逸并持久抑制 HIV-1

• 批准号: 10469169
• 负责人: Katharine June Bar
• 金额: $ 148.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469169
• 关键词: AIDS prevention; Address; Algorithms; Antibodies; Autologous; B-Cell Antigen Receptor; B-Lymphocytes; Bar Codes; Binding Sites; Cellular biology; Clinical Trials; Collection; Combined Modality Therapy; Complement; Data; Data Set; Development; Disease; Epitopes; Evolution; Face; Genetic Drift; Goals; Growth; HIV; HIV-1; In Vitro; Infection; Intervention; Longevity; Maps; Measurement; Measures; Modeling; Molecular Virology; Mutation; Natural Immunity; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasma; Polysaccharides; Population; Prevention; Prevention trial; Resistance; Resource Development; Role; Sampling; Secure; Silicon Dioxide; Testing; Variant; Viral; Viremia; Virus; Virus Replication; Work; adaptive immune response; adaptive immunity; antagonist; clinically relevant; cohort; humanized mouse; improved; in vivo; in vivo evaluation; kinetic model; multidisciplinary; neutralizing antibody; novel; precision medicine; pressure; prevent; rational design; resistance mechanism; response; simian human immunodeficiency virus; viral resistance; virus host interaction

Project Summary/Abstract. Advances in B cell biology and molecular virology have enabled the discovery, characterization, and commercial development of several classes of broadly neutralizing antibodies (bnAbs), with applications for prevention, treatment, and cure of HIV disease are under study. Yet, virus resistance remains the central vulnerability of effective bnAb use. This application proposes to address the problem of bNAb escape by rationally selecting combination bNAb therapy that limits virus escape. We propose to apply lessons from the successful development of combination antiretrovial therapy (cART), whereby bidirectional phenotypic antagonism was exploited. Our multidisciplinary team has secured plasma virus or virus sequences from recent or ongoing prevention and treatment studies of VRC01-class CD4 binding site (CD4bs)-targeting monotherapy, as well as combination therapy with V3 glycan-targeting (Table 1). We will leverage these unique samples to map the in vivo escape pathways of virus replicating in the presence of sub-suppressive levels of these clinically relevant bNAbs (Aim 1). Using the evolving escape variants, we will identify putative complementary bNAbs with maintained or inverse antibody sensitivities from rationally designed panels of candidate bNAbs (Aim 1). We will then characterize the autologous neutralizing antibody (anAb) response in the treatment cohorts, to determine the capacity of anAbs to impede virus escape from administered bNAbs (Aim 2). Finally, we will test the most promising complementary bNAbs to restrict virus escape in vivo in a validated barcoded TF SHIV/NHP model (Aim 3). Our scientific premise is that in vivo mapping of virus escape from bNAbs, identification of complementary bNAbs, defining the role of autologous antibodies, and rigorous in vivo testing in an authentic NHP model will elucidate basic mechanisms of virus resistance to bNAbs and inform more effective use of bNAbs across the HIV prevention, treatment and cure fields. If accomplished we will (i) have defined the sensitivities of escaped viruses from clinical trials to alternate bNAbs, (ii) identified bNAbs that cannot mutually escape using the same pathway, (iii) defined the role of anAbs in bnAb escape and (iv) tested the ability of complementary bnAbs to improve therapy in an authentic NHP model.

项目摘要/摘要。 B细胞生物学和分子病毒学的进步使发现，表征和商业能力 开发几类广泛中和抗体（BNAB）的类别，以及用于预防的应用 正在研究治疗和治愈HIV疾病。然而，病毒抗性仍然是核心脆弱性 有效的BNAB使用。本申请建议通过理性选择解决BNAB逃脱的问题 BNAB疗法的组合限制了病毒逃生。我们建议将成功的课程应用 联合抗逆转疗法（CART）的发展，双向表型拮抗作用是 被利用。我们的多学科团队已从最近或正在进行的 VRC01级CD4结合位点（CD4B）的预防和治疗研究 - 靶向单一疗法以及 与V3聚糖靶向的组合疗法（表1）。我们将利用这些独特的样本来映射 在存在这些临床相关的亚抑制水平的情况下，病毒复制的体内逃生途径 bnabs（目标1）。使用不断发展的逃生变体，我们将使用 从合理设计的候选BNABS面板中维持或反抗体敏感性（AIM 1）。我们将 然后表征治疗队列中自体中和抗体（ANAB）反应，以确定 Anabs阻碍病毒从管理的BNAB中逃脱的能力（AIM 2）。最后，我们将测试最多 有希望的互补BNAB限制了经过验证的条形码TF SHIV/NHP模型的体内病毒逃生 （目标3）。我们的科学前提是病毒逃脱的体内映射，识别 互补的bnabs，定义自体抗体的作用，并在真实的体内测试严格 NHP模型将阐明病毒对BNAB的耐药性的基本机制，并为BNAB的更有效使用提供信息 在预防HIV，治疗和治疗领域。如果完成的话，我们将（i）定义了 从临床试验到替代BNAB的逃脱病毒，（ii）鉴定出无法使用相互逃脱的BNAB 相同的途径（iii）定义了Anabs在BNAB逃生中的作用，并且（iv）测试了互补的能力 在正宗NHP模型中改善治疗的BNAB。