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.

当代广泛中和HIV特异性单抗(BNAbs)有许多 在艾滋病毒-1预防、治疗和治愈方面令人兴奋的应用。BNAbs在HIV感染中的治疗应用 个人正被追求着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 猴-人免疫缺陷病毒(SHIV)感染猕猴体内单抗和联合抗体的研究 显示出显著的有效和持久的病毒抑制，增强了抗艾滋病毒的免疫 响应，以及可能减少的细胞储存池。相比之下，最近的人体临床试验 显示出明显较低的效力和耐久性，对细胞储存库没有影响，并且经常预先存在和 新出现的抗bNAb变异体。临床前SHIV/猕猴实验的不一致结果 人体临床试验强调了bNAb免疫治疗的几个基本问题，以及 一个具有良好特征的HIV潜伏期的SIV/猕猴模型，用于研究它们。 项目1将利用NHP模型中的两个最新进展来阐明Tf的决定因素 希沃克病毒从bNAb免疫疗法中反弹：(I)我们小组发现了一种新的策略来创造致病 保留传播型/方正(Tf)HIV-1env抗原构象和病毒动力学的SHIV 主要HIV-1毒株的持久性特性，以及(Ii)放置无声基因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，并使复杂的建模 病毒动力学、重新激活和反弹。这个项目的一个中心前提是，一个特点很好的 潜伏期和病毒重新激活的条形码Tf Shiv模型将有助于描述病毒的决定因素 反弹并阐明bNAb给药的能力、机制和免疫调节作用。 利用这一新的TF Shiv模型，我们将在以下背景下测试联合bNAb免疫疗法 在ART开始的早期和晚期以及病毒血症时治疗中断。项目1的具体目标是：1) 确定bNab免疫疗法如何改变病毒的重新激活、来源组织和随后的病毒生长；2) 确定中和抵抗的病因和影响；3)确定治疗中断或 BNab免疫疗法改变潜伏期的大小；以及4)确定bNAbs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。 一种新的生物相关的TFSHV模型中的潜伏期和病毒反弹的特征 广泛测试治疗和根除策略。此外，bNAb免疫疗法的测定 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 对宿主免疫反应的影响将为设计未来的bNAb病毒免疫治疗策略提供参考 镇压和铲除。