Project #1 Bar and Shaw

项目

• 批准号: 10224007
• 负责人: Katharine June Bar
• 金额: $ 35.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224007
• 关键词: Address; Affect; Antibodies; Antibody Response; Archives; Autologous; Bar Codes; Biological; Cells; Characteristics; Clinical Trials; Discrimination; Etiology; Future; Generations; Genetic; Goals; Growth; HIV; HIV-1; Human; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Interruption; Kinetics; Lead; Macaca; Macaca mulatta; Measures; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Pathogenicity; Pattern; Plasma; Prevention therapy; Property; Resistance; Rest; Role; SIV; T cell response; T memory cell; Testing; Therapeutic; Tissues; Variant; Viral; Viral reservoir; Viremia; Virus; Virus Replication; cell type; clinical development; clinical efficacy; clinical outcome measures; design; exhaustion; experimental study; immunoregulation; improved functioning; novel; novel strategies; pre-clinical; preclinical study; prevent; reactivation from latency; simian human immunodeficiency virus; therapeutic evaluation; viral rebound

The current generation of broadly neutralizing HIV-specific monoclonal antibodies (bNAbs) have many exciting applications in HIV-1 prevention, therapy, and cure. Therapeutic administration of bNAbs in HIVinfected individuals is being pursued with the overlapping goals of maintaining plasma virus suppression, enabling Fc-mediated clearance of virus-infected cells, and enhancing host immune responses. Preclinical studies of single and combination bNAbs in simian-human immunodeficiency virus (SHIV)-infected macaques have demonstrated remarkably potent and durable virus suppression, augmentation of anti-HIV immune responses, and possible reductions of the cellular reservoir. In contrast, recent human clinical trials have shown markedly less potency and durability, no effect on the cellular reservoir, and frequent pre-existent and emergent bNAb-resistant variants. The discordant results of pre-clinical SHIV/macaque experiments and human clinical trials highlight several fundamental questions underlying bNAb immunotherapy and the need for a well-characterized SHIV/macaque model of HIV latency in which to study them. Project 1 will capitalize on two recent advances in NHP models to elucidate the determinants of TF SHIV rebound from bNAb immunotherapy: (i) our group’s discovery of a novel strategy to create pathogenic SHIVs that retain the antigenic conformation of transmitted/founder (TF) HIV-1 Env and the viral kinetics and persistence properties of primary HIV-1 strains, and (ii) a strategy to place silent genetic tags, or barcodes, within a virus stock, which allows for discrimination of each viral lineage and enables sophisticated modeling of viral kinetics, reactivation and rebound. A central premise of this project is that a well-characterized barcoded-TF SHIV model of latency and virus reactivation will enable delineation of the determinants of viral rebound and elucidate the capabilities, mechanisms, and immunomodulatory effects of bNAb administration. Utilizing this novel TF SHIV model, we will test combination bNAb immunotherapy in the context of treatment interruption after early and late ART initiation and in viremia. Specific Aims of Project 1 are to: 1) determine how bnAb immunotherapy alters virus reactivation, tissues of origin and subsequent virus growth; 2) identify the etiology and impact of neutralization resistance; 3) determine whether treatment interruption or bNAb immunotherapy change the size of the latent reservoir; and 4) determine how bNAbs modulate host antibody and T cell responses. Results from these studies will elucidate the viral kinetics and immunologic characteristics of latency and viral rebound in a novel, biologically relevant TF SHIV model that could facilitate broad testing of therapeutic and eradicative strategies. Further, the determination of bNAb immunotherapy’s clinical efficacy, mechanisms of bNAb mediated virus suppression, effects on the archived viral reservoir, and impact on host immune responses will inform the design of future bNAb immunotherapeutic strategies for virus suppression and eradication.

目前这一代广泛中和的HIV特异性单克隆抗体（bNAb）具有许多抗HIV抗体的特性。 在HIV-1预防、治疗和治愈方面的令人兴奋的应用。HIV感染者中bNAb的治疗性给药 个体被追求的重叠目标是维持血浆病毒抑制， 使Fc介导的病毒感染细胞的清除成为可能，并增强宿主免疫应答。临床前 在猴-人免疫缺陷病毒（SHIV）感染的猕猴中的单一和组合bNAb的研究 已经证明了显着有效和持久的病毒抑制，增强抗艾滋病毒免疫 反应，以及细胞库的可能减少。相比之下，最近的人类临床试验 显示出明显较低的效力和持久性，对细胞库没有影响，并且经常预先存在， 出现的bNAb抗性变体。临床前SHIV/猕猴实验的不一致结果和 人类临床试验强调了bNAb免疫疗法的几个基本问题， 一个充分表征的SHIV/猕猴HIV潜伏期模型，用于研究它们。 项目1将利用NHP模型的两个最新进展来阐明TF的决定因素 BNAb免疫疗法引起的SHIV反弹：（i）我们小组发现了一种新的策略， 保留了传播/创始者（TF）HIV-1 Env的抗原构象和病毒动力学的SHIV， 原代HIV-1毒株的持久性，和（ii）放置沉默遗传标签或条形码的策略， 在病毒库中，这允许区分每种病毒谱系，并能够对 病毒动力学、再活化和反弹。该项目的一个中心前提是， 潜伏期和病毒再活化的条形码-TF SHIV模型将能够描绘病毒的决定因素， 反弹和阐明的能力，机制，和bNAb管理的免疫调节作用。 利用这种新的TF SHIV模型，我们将在以下情况下测试组合bNAb免疫疗法： 在早期和晚期ART启动后以及病毒血症中中断治疗。项目1的具体目标是：1） 确定bnAb免疫疗法如何改变病毒再活化、起源组织和随后的病毒生长; 2） 确定中和抗性的病因和影响; 3）确定是否中断治疗或 bNAb免疫疗法改变潜伏库的大小;以及4）确定bNAb如何调节宿主 抗体和T细胞反应。这些研究的结果将阐明病毒动力学和免疫学 在一个新的，生物学相关的TF SHIV模型中，潜伏期和病毒反弹的特征可以促进 广泛测试治疗和根除战略。此外，bNAb免疫疗法的确定 临床疗效、bNAb介导的病毒抑制机制、对存档病毒库的影响，以及 对宿主免疫应答的影响将为未来针对病毒的bNAb免疫策略的设计提供信息。 镇压和根除。