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.

项目概要 全球有 180 万儿童感染 HIV-1，每年约 180,000 例新感染病例中有一半以上发生 产后通过母乳传播。虽然抗逆转录病毒疗法 (ART) 改善了疾病结果 且传播减少，残余免疫激活在 ART 期间持续存在，而 ART 中断会导致 由于潜伏病毒库，病毒迅速反弹。延迟或防止病毒反弹的干预措施 缺乏抗逆转录病毒治疗对于必须始终接受抗逆转录病毒治疗的儿科人群非常有益 他们的寿命。在成人中，被认为会导致疾病进展的微生物失调在最初的几年内就很明显 HIV-1 感染数周且无法通过 ART 治疗恢复。 HIV感染对身体的影响 发育中的微生物组及其在婴儿疾病进展中的作用尚不明确。此举的目的 提案旨在深入了解 SIV 感染期间的微生物组组成和功能并进行调查 IL-21 作为治疗剂减少感染 SIV 的 ART 抑制的幼年恒河猴微生物失调的效果 猕猴（RM）。 IL-21 驱动 Th17 分化，Th17 是对粘膜免疫至关重要的免疫细胞群 体内平衡和肠上皮屏障功能在早期 HIV/SIV 感染中优先耗尽。 IL-21 最近在成人 RM 中显示出有希望的结果，预计会对免疫产生有利影响 婴儿 HIV-1 感染引起的功能障碍。科学前提是我们的新产后模型 婴儿 RM 中的口腔 SIV 感染和抑制性 ART 将使我们能够生成微生物组的关键数据 IL-21 的组成和功能以及潜在治疗剂的影响。中心假设是通过 通过给予外源性 IL-21 恢复 Th17 CD4+ T 细胞，我们将逆转微生物失调 SIV 感染后发生的情况，导致免疫激活减少和病毒感染减少 ART 中的病毒储存库和 ART 中断后的设定点病毒血症。我们将在下面检验这个假设 具体目标：1) 确定 SIV 感染和 ART 抑制对微生物群发展的影响 在婴儿 RM 中； 2) 确定 IL-21 对感染 SIV 且 ART 抑制的婴儿微生物组的影响 RM。该提案的一个关键特征是使用我们新颖的、高度相关的动物模型来执行受控的 研究可直接转化为未来临床试验的创新免疫方法。我们期望 该提案的研究结果将为我们理解 HIV-1 发病机制提供重要信息 儿科人群的治疗方法。