Project 2: Impact of immune-based intervention on viral rebound in orally SHIV infected infant monkeys

项目 2：免疫干预对经口感染 SHIV 的幼猴病毒反弹的影响

基本信息

批准号：
10194353
负责人：
Genevieve Giny Fouda Amou ou
金额：
$ 24.04万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-24 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194353
关键词：
Activities of Daily Living Adjuvant Aftercare Animal Model Animals Antibodies Antibody Response Antiviral Agents Binding Biological Markers Breast Feeding CD8-Positive T-Lymphocytes Characteristics Child Childhood DNA DNA/MVA vaccine Development Diagnosis Disease remission Evaluation HIV Human Human Milk Immune Immune response Immune system Immunization Immunize Immunotherapeutic agent Infant Infection Interruption Intervention Kinetics Leadership Macaca mulatta Measurement Measures Modeling Monkeys Monoclonal Antibodies Oral Passive Immunization Peripheral Blood Mononuclear Cell Plasma Population Preparation Reaction Time Reagent Role SHIV vaccine Statistical Data Interpretation T cell response T-Lymphocyte TNFSF5 gene Testing Therapeutic Intervention Time Universities Vaccination Vaccine Therapy Vaccines Viral Antibodies Viral Load result Viral reservoir Virus antiretroviral therapy base design immunological intervention infant infection lymph nodes nonhuman primate passive antibodies pediatric human immunodeficiency virus pediatric human immunodeficiency virus infection postnatal programs service utilization simian human immunodeficiency virus standard of care stem synergism transmission process viral rebound virology

项目摘要

ABSTRACT – Project 2 (Leader: Dr. Genevieve Fouda, Duke University) More than 1.8 million children world-wide live with HIV, and every year more than 150,000 new pediatric HIV infections occur. Current standard of care commits HIV-infected children to lifelong, daily antiretroviral treatment (ART). However, ART does not cure HIV due to the persistence of virus reservoirs that re-establish infection following treatment interruption. Therapeutic interventions that lower the size of the virus reservoir could delay virus rebound when ART is interrupted. Such reservoir reduction can be achieved by very early ART initiation, but this is not practical for the roughly half of pediatric HIV cases stemming from postnatal infection via breast milk HIV transmission because their diagnosis is delayed. Thus, postnatally infected children would benefit greatly from development of adjunct therapies, including immune-based strategies. Indeed, studies have indicated that antibody passive immunization and therapeutic vaccination can impact virus reservoirs, but their relevance and effect in the maturating infant immune system remains unknown. A first step toward development of immunotherapeutic interventions for postnatally infected infants thus will require identifying the immune mechanisms associated with virus control after breast milk transmission. Thus the objective of this Project is to identify immune correlates of virus rebound in the setting of breast milk transmission. Our central hypothesis is that enhancement of specific antiviral immune responses in ART- treated, simian-human immunodeficiency virus (SHIV)-infected infant rhesus macaques (RMs), either through antibody passive immunization or through vaccination, will reduce the virus reservoir and delay virus rebound after treatment interruption. We propose the following aims: 1) Assess kinetics of virus-specific immune responses in ART treated SHIV-infected infant RMs; 2) Define the impact of adjunct therapy with polyclonal polyfunctional antiviral antibodies on virus rebound in an infant RM model of breast milk transmission and ART; and 3) Evaluate the impact of enhancing T cell responses through vaccination on virus rebound in SHIV- infected ART-treated infant RMs. This Project will interact with the proposed Program's other Project and utilize the services of the Administrative and Statistical Core, the Nonhuman Primate Core, and Virology Core. This Project will identify immune correlates associated with reservoir clearance and/or delay in virus rebound in a highly relevant animal model of postnatal transmission and thereby guide design of pediatric-specific immune- based interventions towards an HIV functional cure.

摘要 – 项目 2（负责人：杜克大学 Genevieve Fouda 博士）全球有超过 180 万儿童感染艾滋病毒，每年新增超过 15 万儿童艾滋病毒感染者目前的护理标准要求感染艾滋病毒的儿童终生每天接受抗逆转录病毒治疗。然而，由于重新建立的病毒储存库持续存在，ART 无法治愈 HIV。治疗中断后的感染。当 ART 中断时，可以延缓病毒反弹。启动抗逆转录病毒治疗，但这对于大约一半产后产生的儿童艾滋病毒病例来说并不实际通过母乳感染艾滋病毒，因为诊断被延迟，因此产后感染。儿童将从辅助疗法（包括基于免疫的策略）的开发中受益匪浅。事实上，研究表明抗体被动免疫和疫苗接种治疗可以影响病毒储存库，但它们在成熟婴儿免疫系统中的相关性和影响仍然未知。因此，为产后感染婴儿开发免疫治疗干预措施的第一步将是因此需要与母乳传播后病毒控制相关的免疫机制。该项目的目标是确定母乳环境中病毒反弹的免疫相关性我们的中心假设是 ART 中特异性抗病毒免疫反应的增强。治疗后，感染猿猴人类免疫缺陷病毒（SHIV）的幼年恒河猴（RM），或者通过抗体被动免疫或通过疫苗接种，会减少病毒储存量并延缓病毒反弹治疗中断后，我们提出以下目标：1）评估病毒特异性免疫的动力学。 ART 治疗的 SHIV 感染婴儿 RM 的反应；2) 定义多克隆辅助治疗的影响；多功能抗病毒抗体对母乳传播和 ART 婴儿 RM 模型中病毒反弹的影响； 3) 评估通过疫苗接种增强 T 细胞反应对 SHIV 病毒反弹的影响受感染的接受 ART 治疗的婴儿 RM 该项目将与拟议计划的其他项目互动并利用。行政和统计核心、非人类灵长类核心和病毒学核心的服务。项目将确定与病毒储存库清除和/或病毒反弹延迟相关的免疫相关性。产后传播高度相关的动物模型，从而指导儿科特异性免疫的设计基于艾滋病毒功能性治愈的干预措施。