IL-21 as a Therapeutic to Reduce Immune Activation and Normalize Microbial Dysbiosis in SIV-Infected ART-Suppressed Infant Macaques

IL-21 作为一种治疗方法，可减少 SIV 感染的 ART 抑制的婴儿猕猴的免疫激活并使微生物失调正常化

• 批准号: 9927317
• 负责人: Katherine M Bricker
• 金额: $ 4.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2023-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927317
• 关键词: 3 year old; Adult; Age; Animal Model; Antiviral Therapy; Birth; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Childhood; Clinical Trials; Controlled Study; Data; Development; Digestion; Disease; Disease Outcome; Disease Progression; Disease remission; Face; Functional disorder; Funding; Future; Gastrointestinal tract structure; HIV; HIV Infections; HIV-1; Homeostasis; Human Milk; Immune; Immune System Diseases; Immunologics; Immunotherapeutic agent; Infant; Infection; Inflammation; Interruption; Intervention; Laboratories; Longevity; Macaca; Macaca mulatta; Maintenance; Metabolism; Mississippi; Modeling; Mucosal Immune System; Mucous Membrane; Oral; Pathogenesis; Pathogenicity; Population; Regulation; Residual state; Role; SIV; Safety; Testing; Therapeutic; Viral; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Latency; Work; antiretroviral therapy; base; cytokine; design; dysbiosis; immune activation; immunological intervention; improved; infancy; innovation; insight; intestinal epithelium; microbial; microbiome; microbiome alteration; microbiome composition; neonatal infection; nonhuman primate; novel; novel therapeutics; pediatric patients; postnatal; prevent; restoration; side effect; simian human immunodeficiency virus; translational study; transmission process; viral rebound; virology

PROJECT SUMMARY Globally, 1.8 million children are living with HIV-1 and over half of the ~180,000 new infections annually occur postnatally through breast milk transmission. While antiretroviral therapy (ART) has improved disease outcome and reduced transmission, residual immune activation persists during ART and interruption of ART leads to rapid viral rebound due to the latent viral reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial to the pediatric population who must remain on ART throughout their lifespan. In adults, microbial dysbiosis thought to drive disease progression is evident within the first few weeks of HIV-1 infection and is not restored through ART administration. The effect of HIV infection on the developing microbiome and its role in disease progression of infants is not well defined. The objective of this proposal is to provide insight into the microbiome composition and function during SIV infection and investigate the effect of IL-21 as a therapeutic to reduce microbial dysbiosis in SIV-infected ART-suppressed infant rhesus macaques (RMs). IL-21 drives Th17 differentiation, a population of immune cells critical to mucosal immune homeostasis and intestinal epithelial barrier function that are preferentially depleted in early HIV/SIV infection. IL-21 recently showed promising results in adult RMs and is predicted to favorably impact the immune dysfunction induced by HIV-1 infection in infants. The scientific premise is that our novel model of postnatal oral SIV infection and suppressive ART in infant RMs will allow us to generate key data on microbiome composition and function and the impact of a potential therapeutic, IL-21. The central hypothesis is that by restoring Th17 CD4+ T cells through administration of exogenous IL-21, we will reverse microbial dysbiosis that occurs following SIV infection resulting in reduced immune activation and a reduction in both viral reservoirs on ART and set point viremia after ART interruption. We will test this hypothesis in the following Specific Aims: 1) To determine the impact of SIV infection and ART suppression on microbiome development in infant RMs; 2) To determine the impact of IL-21 on the microbiome in SIV-infected ART-suppressed infant RMs. A key feature of this proposal is the use of our novel, highly relevant animal model to perform controlled studies of an innovative immune-based approach that is directly translatable to future clinical trials. We expect that the findings from this proposal will critically inform our understanding of HIV-1 pathogenesis and therapeutic approaches in the pediatric population.

项目摘要 在全球范围内，有180万儿童患有HIV-1，每年发生约180,000个新感染中的一半以上 产后通过母乳传播。而抗逆转录病毒疗法（ART）改善了疾病结果 降低传播，在艺术期间残留免疫激活以及艺术中断导致 由于潜在的病毒储存库而引起的快速病毒反弹。延迟或防止病毒反弹的干预措施 缺乏艺术将对必须在整个过程中保持艺术的儿科人群非常有益 他们的寿命。在成年人中，在前几个中，显而易见的微生物营养不良被认为驱动疾病进展是显而易见的 HIV-1的几周感染，未通过艺术管理恢复。艾滋病毒感染对 发展微生物组及其在婴儿疾病进展中的作用尚未得到很好的定义。这个目的 提案是为SIV感染期间的微生物组组成和功能提供深入了解并进行研究 IL-21作为降低SIV感染艺术抑制的婴儿恒河生微生物营养不良的治疗作用 猕猴（RMS）。 IL-21驱动Th17分化，这是对粘膜免疫至关重要的免疫细胞群 在早期HIV/SIV感染中优先耗尽的稳态和肠上皮屏障功能。 IL-21最近在成人RMS中显示出令人鼓舞的结果，预计会对免疫产生有益的影响 HIV-1感染引起的婴儿功能障碍。科学的前提是我们新颖的产后模型 婴儿RMS中的口服SIV感染和抑制作用将使我们能够生成微生物组的关键数据 组成和功能以及潜在治疗的IL-21的影响。中心假设是 通过给予外源IL-21恢复Th17 CD4+ T细胞，我们将逆转微生物失调 这是在SIV感染后发生的，导致免疫激活降低和两种病毒的降低 艺术中断后的艺术和设定点病毒血症的水库。我们将在以下来检验这一假设 具体目的：1）确定SIV感染和ART抑制对微生物组发展的影响 在婴儿RMS中； 2）确定IL-21对SIV感染的ART抑制婴儿的微生物组的影响 RMS。该提案的关键特征是使用我们的小说，高度相关的动物模型执行受控 基于创新的免疫方法的研究直接转化为未来的临床试验。我们期望 该提案的发现将批评我们对HIV-1发病机理的理解和 小儿人群的治疗方法。