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.

当前的广泛中和HIV特异性单克隆抗体（BNAB）的一代具有许多 HIV-1预防，治疗和治疗中的令人兴奋的应用。 Hivinted的BNAB的治疗性给药 个人正在追求维持血浆病毒抑制的重叠目标， 使FC介导的病毒感染细胞清除，并增强宿主免疫反应。临床前 猿猴免疫缺陷病毒（SHIV）感染的猕猴的单一和组合BNAB的研究 已经表现出非常潜在且耐用的病毒抑制，抗HIV免疫的增强 反应，并可能减少细胞储层。相反，最近的人类临床试验具有 显示出明显较小的效力和耐用性，对蜂窝储层没有影响，并且经常存在，并且 紧急抗BNAB的变体。临床前湿液/猕猴实验的不一致结果和 人类的临床试验突出了BNAB免疫疗法的基本几个基本问​​题 艾滋病毒潜伏期的特征良好的Shiv/猕猴模型，可以在其中进行研究。 项目1将利用NHP模型的两个最新进展，以阐明TF的确定性 BNAB免疫疗法反弹的SHIV反弹：（i）我们小组发现的一种新型策略来创造致病性 保留传播/创始人（TF）HIV-1 Env和病毒动力学的抗原构象的SHIV和 原发性HIV-1菌株的持久性特性，以及（ii）放置无声遗传标签或条形码的策略， 在病毒库存中，可以区分每个病毒谱系，并实现复杂的建模 病毒动力学，重新激活和反弹。该项目的一个主要前提是一个符合特点的 条形码-TF的延迟和病毒重新激活模型将使病毒的确定剂描述 反弹并阐明BNAB给药的能力，机制和免疫调节作用。 利用这种新颖的TF SHIV模型，我们将在 早期和晚期倡议和病毒血症的治疗中断。项目1的具体目标是：1） 确定BNAB免疫疗法如何改变病毒重新激活，原产组织和随后的病毒生长； 2） 确定神经化抗性的病因和影响； 3）确定治疗中断还是 BNAB免疫疗法改变潜在储层的大小； 4）确定BNABS如何调节主机 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 潜伏期和病毒反弹的特征在一种新颖的生物学相关的TF SHIV模型中，可以促进 对理论和放射性策略的广泛检验。此外，确定BNAB免疫疗法的 临床有效性，BNAB介导的病毒抑制的机制，对存档病毒库的影响以及 对宿主免疫反应的影响将为未来的BNAB免疫治疗策略的设计提供信息 抑制和消除。