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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要。 B细胞生物学和分子病毒学的进展使得能够发现、表征和商业化。开发几类广泛中和抗体（bnAb），用于预防，艾滋病的治疗和治愈正在研究中。然而，病毒抵抗力仍然是核心脆弱性 bnAb的有效使用。本申请提出通过合理选择来解决bNAb逃逸的问题限制病毒逃逸的bNAb联合疗法。我们建议借鉴成功经验，联合抗逆转录病毒治疗（cART）的发展，其中双向表型拮抗作用，被剥削我们的多学科团队已经从最近或正在进行的研究中获得了血浆病毒或病毒序列。 VRC 01类CD 4结合位点（CD 4 bs）靶向单药治疗的预防和治疗研究，以及图1示出了与V3聚糖靶向的联合疗法的实施例（表1）。我们将利用这些独特的样本来绘制在这些临床相关的亚抑制水平存在下病毒复制的体内逃逸途径 bNAbs（Aim 1）。使用进化的逃逸变体，我们将鉴定推定的互补bNAb，维持或逆转来自合理设计的候选bNAb组的抗体敏感性（目的1）。我们将然后表征治疗队列中的自体中和抗体（anAb）应答，以确定抗体阻止病毒从施用的bNAb逃逸的能力（目的2）。最后，我们将测试最在经验证的条形码TF SHIV/NHP模型中有希望限制病毒体内逃逸的互补bNAb (Aim 3）。我们的科学前提是，在体内绘制病毒从bNAb逃逸的图谱，鉴定互补bNAb，定义自体抗体的作用，以及在真实的 NHP模型将阐明病毒对bNAb的抗性的基本机制，并为更有效地使用bNAb提供信息在艾滋病预防、治疗和治愈领域。如果完成，我们将（i）确定以下方面的敏感性：病毒从临床试验中逃逸到替代bNAb，（ii）确定了无法使用相互逃逸的bNAb 相同的途径，（iii）确定了anAb在bnAb逃逸中的作用，以及（iv）测试了互补的能力。 bnAb以改善真实NHP模型中的治疗。