Immune interventions in SIV-infected ART-suppressed infant macaques

摘要 在世界范围内，有180万儿童感染艾滋病毒-1，每年约有15万新的儿科感染， 其中大约一半是由于在母乳喂养期间传播艾滋病毒-1造成的。虽然抗逆转录病毒治疗 (ART)极大地降低了HIV-1感染的死亡率和发病率，但由于病毒在 潜伏储集层。在缺乏抗逆转录病毒治疗的情况下减少持久性宿主和促进病毒学控制的策略 (即，艾滋病毒-1的缓解)将极大地惠及感染艾滋病毒-1的婴儿和儿童，他们现在必须每天服用 ART从确诊之时就贯穿了他们的一生。 这项提案的目标是测试减少残留免疫激活和/或 增强感染SIV的ART治疗婴儿恒河猴(RMS)的抗病毒免疫反应。我们的 科学前提是我们的出生后口腔SIV感染的新模型和婴儿RMS的抑制艺术 将使我们能够生成关于免疫干预对残余免疫激活的影响的关键数据， ART停用后的抗病毒免疫反应、病毒库和病毒反弹。这个 我们将测试的干预措施，IL-21和AD26/MVA治疗性疫苗与TLR7刺激(TV TLR7)， 最近在成人RMS中显示了有希望的结果，并被预测对免疫功能障碍有有利的影响 婴儿感染HIV-1所致。中心假说是，通过将这种免疫功能障碍作为目标 减少残留免疫激活和/或增强病毒特异性免疫反应，我们将减少病毒 并促进病毒学控制。我们将检验这一假设是否具有以下具体目的：1) 确定IL-21或TV TLR7对SIV感染的ART抑制的婴儿RMS的免疫学影响；2) 评估IL-21或TV TLR7是否以及在多大程度上减少了SIV感染的ART抑制的病毒库 婴儿RMS；以及3)确定IL-21或TV TLR7是否以及在多大程度上导致延迟病毒 SIV感染的婴儿RMS在ART阻断后出现病毒血症反弹或降低的设定点。这是它的一个关键特征 建议是，通过使用我们新的、高度相关的SIV感染和ART治疗的动物模型，我们 能够对病毒库和治疗中断进行深入分析，这是不可能的 儿科受试者的行为。我们希望这个项目的发现能为HIV-1的治疗工作提供重要的指导 在儿科人群中。

ABSTRACT Worldwide, there are 1.8 million children living with HIV-1 and ~150,000 new pediatric infections per year, approximately half of which occur due to HIV-1 transmission during breastfeeding. While antiretroviral therapy (ART) greatly reduces mortality and morbidity of HIV-1 infection, it is not a cure due to virus persistence in latent reservoirs. Strategies to reduce the persistent reservoir and promote virologic control in absence of ART (i.e., HIV-1 remission) would greatly benefit HIV-1-infected infants and children that now must remain on daily ART from the time of diagnosis through their entire life span. The Objective of this proposal is to test interventions that decrease residual immune activation and/or enhance antiviral immune responses in SIV-infected ART-treated infant rhesus macaques (RMs). Our 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 the impact of immune interventions on residual immune activation, antiviral immune responses, virus reservoirs, and viral rebound following ART discontinuation. The interventions we will test, IL-21 and Ad26/MVA therapeutic vaccination with TLR7 stimulation (TV+TLR7), recently showed promising results in adult RMs and are predicted to favorably impact the immune dysfunction induced by HIV-1 infection in infants. The Central Hypothesis is that by targeting this immune dysfunction to reduce residual immune activation and/or boost virus-specific immune responses, we will decrease viral reservoirs and promote virologic control. We will test this hypothesis is in the following Specific Aims: 1) To determine the immunological impact of IL-21 or TV+TLR7 in SIV-infected ART-suppressed infant RMs; 2) To assess whether and to what extent IL-21 or TV+TLR7 reduces viral reservoirs in SIV-infected ART-suppressed infant RMs; and 3) To determine whether and to what extent IL-21 or TV+TLR7 results in delayed virus rebound or reduced viremia set point after ART interruption in SIV-infected infant RMs. A key feature of this proposal is that, by using our novel, highly relevant animal model of SIV infection and ART treatment, we are able to perform in-depth analyses of virus reservoirs and treatment interruption that would be impossible to conduct in pediatric participants. We expect the findings from this Project to critically inform HIV-1 cure efforts in the pediatric population.