Immune interventions in SIV-infected ART-suppressed infant macaques

对感染 SIV 且 ART 抑制的幼年猕猴进行免疫干预

• 批准号: 9395535
• 负责人: Ann M Chahroudi
• 金额: $ 85.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395535
• 关键词: Adherence; Adolescence; Adult; Adverse effects; Anatomy; Animal Model; Antiviral Agents; Breast Feeding; CD8-Positive T-Lymphocytes; Cell Cycle Kinetics; Cells; Cellular Immunity; Child; Childhood; Clinical; Comparative Study; Controlled Study; Data; Diagnosis; Disease remission; Ethics; Gastrointestinal tract structure; Genes; Goals; HIV; HIV-1; Immune; Immune System Diseases; Immune System and Related Disorders; Immune Targeting; Immune response; Immune system; Immunization; Immunologic Tests; Immunologics; Infant; Infection; Inflammation; Interruption; Intervention; Longevity; Macaca; Macaca mulatta; Measures; Modeling; Morbidity - disease rate; Mucosal Immunity; Oral; Participant; Patients; Perinatal; Population; Research; Residual state; Risk; SIV; Safety; Sexual Partners; TLR7 gene; Testing; Therapeutic; Time; Vaccination; Viral; Viral reservoir; Viremia; Virus; Work; antiretroviral therapy; base; cost; design; immune activation; immunological intervention; immunoregulation; improved; mortality; neutralizing antibody; novel; novel strategies; novel therapeutics; pediatric patients; postnatal; prevent; therapeutic vaccine; translational study; transmission process; viral rebound; virology

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.

摘要 全世界每年有180万儿童感染HIV-1，约15万新发儿科感染， 其中大约一半是由于母乳喂养期间HIV-1传播而发生的。虽然抗逆转录病毒治疗 (ART)大大降低了HIV-1感染的死亡率和发病率，但由于病毒在体内的持续存在， 潜在储层在没有ART的情况下减少持久性储存库并促进病毒学控制的策略 (i.e., HIV-1缓解）将极大地有益于现在必须每天保持的HIV-1感染的婴儿和儿童 ART从诊断的时间到他们的整个生命周期。 本提案的目的是测试降低残留免疫激活和/或 增强SIV感染ART治疗的幼年恒河猴（RM）的抗病毒免疫应答。我们 科学的预测是，我们在婴儿RM中的出生后口腔SIV感染和抑制性ART的新模型 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， 抗病毒免疫应答、病毒储库和ART停药后病毒反弹。的 我们将测试IL-21和Ad 26/MVA治疗性疫苗接种与TLR 7刺激（TV+ TLR 7）， 最近在成人RM中显示出有希望的结果，并预计将对免疫功能障碍产生有利影响 HIV-1感染的婴儿。中心假设是，通过靶向这种免疫功能障碍， 减少残余免疫激活和/或增强病毒特异性免疫应答，我们将减少病毒感染。 水库和促进病毒控制。我们将测试这一假设是在以下具体目的：1） 确定IL-21或TV+ TLR 7在SIV感染的ART抑制的婴儿RM中的免疫学影响; 2） 评估IL-21或TV+ TLR 7是否以及在多大程度上减少了SIV感染的ART抑制患者中的病毒储库。 3）确定IL-21或TV+ TLR 7是否以及在多大程度上导致延迟的病毒感染 SIV感染的婴儿RM在ART中断后病毒血症设定点反弹或降低。其中一个关键特征是， 我们的建议是，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， 能够对病毒储存库和治疗中断进行深入分析， 在儿科参与者中进行。我们希望该项目的发现能为HIV-1治疗工作提供重要信息 在儿科人群中。