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

• 批准号: 10360198
• 负责人: Genevieve Giny Fouda Amou ou
• 金额: $ 36.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360198
• 关键词: Project; Impact; immune; based; intervention; Project; Impact; immune; based; intervention

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：杜克大学的吉纳维芙·福达博士） 全球范围内有超过180万儿童的艾滋病毒生活，每年有超过150,000个新的儿科艾滋病毒 发生感染。当前的护理标准委托感染艾滋病毒的儿童终生，每日抗逆转录病毒 治疗（艺术）。但是，由于病毒库的持续存在，艺术无法治愈艾滋病毒 治疗中断后的感染。降低病毒研究器大小的治疗干预措施 当艺术中断时，可能会延迟病毒反弹。这种储层减少可以很早就实现 艺术倡议，但这对于大约一半的小儿艾滋病毒案件而言是不切实际的 通过母乳艾滋病毒传播感染，因为它们的诊断延迟。那是产后感染的 儿童将从辅助疗法的发展（包括基于免疫的策略）中受益匪浅。 实际上，研究表明抗体被动免疫抑制和治疗疫苗接种会影响 病毒储层，但它们在成熟的婴儿免疫系统中的相关性和作用仍然未知。一个 因此，为产后感染的婴儿开发免疫治疗干预措施的第一步将 需要确定母乳传播后与病毒控制相关的免疫力学。那 该项目的目的是识别母乳中病毒反弹的免疫相关性 传播。我们的中心假设是，在艺术中增强了特定抗病毒药免疫复杂 经过治疗的，猿猴 - 人类免疫缺陷病毒（SHIV）感染的婴儿恒河猕猴（RMS），要么通过 抗体被动免疫抑制或通过疫苗接种，将减少病毒储量并延迟病毒反弹 治疗中断后。我们提出以下目的：1）评估病毒特异性免疫的动力学 ART治疗的Shiv感染的婴儿RMS的反应； 2）定义辅助治疗对多克隆的影响 婴儿RM母乳传播和艺术模型中病毒反弹的多功能抗病毒抗体； 3）评估通过疫苗接种对SHIV-中病毒反弹的疫苗接种增强T细胞反应的影响 感染了经艺术治疗的婴儿RMS。该项目将与拟议程序的其他项目互动并利用 行政和统计核心，非人类灵长类动物核心以及病毒学核心的服务。这 项目将识别与储层清除相关的免疫定位和/或病毒延迟反弹 高度相关的产后传播动物模型，从而指导小儿特异性免疫的设计 基于HIV功能治疗的干预措施。