The origin, predictors, and immune correlates of viral rebound in orally SHIV infected infant monkeys

摘要-整体(萨莉·佩尔马，派；杜克大学) 全世界有近200万儿童感染艾滋病毒，每年有超过15万名儿童感染艾滋病毒 感染就会发生。在这些新感染中，产后母乳传播至少占到一半。当前 护理标准要求感染艾滋病毒的儿童接受终生、每日抗逆转录病毒治疗(ART)。解药就是 需要为感染艾滋病毒的儿童提供没有医疗并发症、药物负担和 与HIV-1感染相关的社会耻辱。虽然早期开始抗逆转录病毒治疗会导致病毒的延长 由于病毒库的持久性，病毒在停止治疗后会反弹。然而， 减少或消除病毒库的战略有望导致长期缓解，因为 通过两年多的无抗逆转录病毒治疗的减刑证明了这一点，该案件被称为 密西西比州的宝宝。使用高度相关的动物模型，我们计划的总体目标是定义起源， 出生后感染婴儿中病毒反弹的动力学和预测因素，以及评估 以免疫为基础的干预措施，以根除儿童艾滋病毒宿主。我们的中心假设是 通过生物标志物的测量，可以预测出生后感染婴儿的病毒反弹动力学。 (项目1)，并可通过加强抗病毒体液免疫和T细胞免疫来扩大(项目2)。 具体地说，我们将使用儿童艾滋病毒感染的高度翻译动物模型和长期ART 治疗以实现以下特定目标：1)确定病毒的来源、动力学和预测因素 在我们的出生后感染的动物模型中，长期应用ART治疗后的反弹；2)确定 广谱中和抗体和T细胞疫苗被动免疫预防病毒反弹 出生后感染的动物模型；以及3)开发一个数学模型，它将定义主要的 病毒反弹的影响因素及免疫干预的潜在疗效 出生后感染。成功完成，该计划将使用我们高度翻译的动物模型来 独一无二地定义病毒反弹的组织来源、动力学和病毒序列，指导开发和 评估针对儿童的HIV治疗策略；定义可用于临床预测病毒的生物标记物 以及评估基于免疫的干预措施对病毒反弹的影响。总而言之，这些结果将 帮助指导设计被动和主动疫苗策略，以实现人类长期缓解或治愈 婴儿。

ABSTRACT – Overall (Sallie Permar, PI; Duke University) Almost 2 million children are infected with HIV worldwide, and every year more than 150,000 new pediatric HIV infections occur. Postnatal breast milk transmission accounts for at least half of these new infections. Current standard of care commits HIV-infected children to lifelong, daily antiretroviral treatment (ART). A cure is needed to provide HIV-infected children a life without the medical complications, pharmacological burden, and social stigma associated with HIV-1 infection. While early initiation of ART leads to prolonged virus suppression, the virus rebounds after treatment cessation due to the persistence of virus reservoirs. However, there is hope that strategies to reduce or eliminate virus reservoirs could lead to long-term remission, as demonstrated by the over two-year ART-free remission that was demonstrated in the case known as `the Mississippi baby'. Using a highly relevant animal model, the overall goal of our Program is to define the origin, kinetics, and predictors of viral rebound in postnatally-infected infants, as well as assess the potential impact of immune-based interventions to eradicate pediatric HIV reservoirs. Our central hypothesis is that the origin and kinetics of viral rebound in postnatally infected infants can be predicted through biomarker measurement (Project 1) and can be extended through the enhancement of antiviral humoral and T cell immunity (Project 2). Specifically, we will use a highly translational animal model of pediatric HIV infection and long-term ART treatment to accomplish the following Specific Aims: 1) Define the origin, kinetics, and predictors of viral rebound following long term ART treatment in our animal model of postnatal infection; 2) Define the impact of passive immunization with broadly-neutralizing antibodies and T cell-based vaccine on viral rebound in our animal model of postnatal infection; and 3) Develop a mathematical model that will define the primary contributing factors and the potential efficacy of immune-based interventions on viral rebound following postnatal infection. Successfully completed, this Program will use our highly translational animal model to uniquely define the tissue origin, kinetics, and viral sequences of viral rebound, guiding development and evaluation of pediatric-specific HIV cure strategies; define biomarkers that can be used to clinically predict viral rebound; and evaluate the impact of immune-based interventions on viral rebound. Together, these results will help guide the design of passive and active vaccine strategies to achieve long-term remission or cure in human infants.