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

项目摘要 在全球范围内，有180万儿童感染了HIV-1，在每年约18万例新感染病例中， 产后通过母乳传播。虽然抗逆转录病毒疗法（ART）改善了疾病的结果， 和减少的传播，残留的免疫激活在ART期间持续存在，ART的中断导致 由于潜伏的病毒库，病毒迅速反弹。延缓或预防病毒反弹的干预 不使用ART将对必须在整个过程中保持ART的儿科人群非常有益。 他们的寿命。在成年人中，被认为是推动疾病进展的微生物生态失调在最初的几个 艾滋病毒-1感染后的几周内，并没有通过抗逆转录病毒治疗恢复。艾滋病病毒感染对 发育中的微生物组及其在婴儿疾病进展中的作用尚未明确。的目的 该提案旨在深入了解SIV感染期间的微生物组组成和功能，并研究 IL-21治疗SIV感染的ART抑制的恒河猴幼猴中微生物生态失调的效果 猕猴（RM）。IL-21驱动Th 17分化，这是一群对粘膜免疫至关重要的免疫细胞 体内平衡和肠上皮屏障功能，这些功能在早期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，并且预计将有利地影响免疫系统。 HIV-1感染引起的婴儿功能障碍。科学的前提是，我们的新模型产后 在婴儿RM中的口服SIV感染和抑制性ART将使我们能够获得关于微生物组的关键数据， 组成和功能以及潜在治疗剂IL-21的影响。核心假设是， 通过给予外源性IL-21恢复Th 17 CD 4 + T细胞，我们将逆转微生物生态失调 SIV感染后发生的免疫反应，导致免疫激活减少， 在ART中断后的设定点病毒血症。我们将在下面测试这个假设 具体目的：1）确定SIV感染和ART抑制对微生物组发育的影响 2）确定IL-21对SIV感染ART抑制婴儿中微生物组的影响 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 研究一种创新的基于免疫的方法，可直接转化为未来的临床试验。我们预计 这项提案的发现将为我们对HIV-1发病机制的理解提供重要信息， 儿科人群的治疗方法。

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.