Pediatric Adolescent Virus Elimination (PAVE) Martin Delaney Collaboratory

儿科青少年病毒消除 (PAVE) Martin Delaney 合作实验室

• 批准号: 10313520
• 负责人: Ann M Chahroudi
• 金额: $ 573.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313520
• 关键词: 15 year old; Active Immunization; Address; Adherence; Adolescent; Adolescent and Young Adult; Adult; Aftercare; Age; Antibody Therapy; Award; Biological Markers; Biological Models; Biology; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Collaborations; Communities; Country; Cultural Diversity; Data; Development; Disease remission; Epidemic; Epigenetic Process; Ethics; Evolution; Exhibits; Faculty; Feedback; Fostering; Future; Gender; Generations; Goals; HIV; HIV-1; Human; Image; Immune; Immune Targeting; Immune system; Immunity; Immunization; Immunologic Markers; Immunologics; Immunotherapeutic agent; Industry; Infant; Infection; International; Interruption; Intervention; Intervention Trial; Investigation; Knowledge; Leadership; Life; Measures; Mediating; Mission; Modeling; Monitor; Myeloid Cells; Natural Killer Cells; Oregon; Passive Immunization; Perinatal Infection; Plasma; Population; Pre-Clinical Model; Predisposition; Prevention; Primates; Research; Research Personnel; Resources; Rest; Role; Safety; Sampling; Science; Shock; Structure; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Vertical Disease Transmission; Viral; Viral reservoir; Virus; Vision; Work; aged; antiretroviral therapy; base; career development; cohort; collaboratory; combat; community engagement; cost; efficacy clinical trial; imaging modality; industry partner; infant infection; insight; latent HIV reservoir; literacy; meetings; memory CD4 T lymphocyte; multidisciplinary; neutralizing antibody; novel; novel strategies; novel therapeutics; pediatric human immunodeficiency virus; perinatal HIV; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; programs; purge; response; side effect; social stigma; therapy duration; viral rebound; virology; young adult

ABSTRACT The immediate establishment of the latent HIV-1 reservoir in resting memory CD4+ T cells precludes HIV-1 cure, compelling ART for a lifetime in children. The mission of the PAVE Collaboratory is to use cutting-edge science to establish a deep and broad understanding of the immunopathogenesis of pediatric HIV-1 reservoirs, across the age spectrum, and to demonstrate preclinical safety and efficacy of novel therapeutics to eradicate reservoirs and control rebound that will pave the way for future interventional human studies toward a lifetime of sustained HIV-1 control off ART. We hypothesize that the unique features of the infant immune system at the time of reservoir establishment impact the characteristics of long-term virus persistence, susceptibility to immune- mediated clearance, and reactivation that are distinct from adult infections, warranting in-depth investigation to inform cure therapeutics suitable for children. We will test this hypothesis and execute the PAVE Scientific Agenda through accomplishment of the following Specific Aims: 1. Define the establishment and evolution of the HIV latent reservoir in perinatal infection. 2. Enhance pediatric immunity and broadly neutralizing antibody (bNAb) delivery to achieve post-treatment control of HIV-1 off ART. 3. Deploy immune-targeted strategies to eliminate virus reservoirs. 4. Optimize virologic, immunologic, and imaging methods to assess efficacy of HIV-1/S(H)IV cure interventions. 5. Foster community engagement in pediatric HIV cure research. The PAVE program is multidisciplinary, multicultural, and iterative with a nimble structure encompassed by four highly synergistic Research Foci and a domestic and international community program that will rapidly incorporate new scientific directions and feedback from our stakeholders. The PAVE leadership team spans diverse scientific expertise and exhibits additional diversity in terms of gender, academic rank, and country of origin. Each of the Research Foci also includes junior faculty co-Investigators to facilitate their career development within the HIV-1 research space. Through the collective efforts of our scientific leadership, Executive Committee, Scientific Advisory Board, investigators, industry partners, network collaborations, and domestic and international community program, PAVE anticipates meeting the following overall milestones of: 1) understanding early life immunity and early antiretroviral treatment on the composition and stability of the latent reservoir, including in naïve T cells, and potential for HIV-1 remission; 2) eliminating of these reservoirs in pre-clinical studies of immune-targeted strategies; 3) defining the role of myeloid cells in HIV-1 persistence and rebound, including in the CNS; 4) establishing novel approaches to enhance pediatric immunity through active and passive immunization; 5) developing cutting-edge approaches to quantify and monitor proviral reservoirs to measure clinical trial efficacy, and 6) promoting active community engagement in pediatric HIV-1 cure research. These milestones will help achieve the vision of sustained ART-free control of HIV-1 replication in pediatric populations.

抽象的 静息记忆 CD4+ T 细胞中潜伏的 HIV-1 储存库的立即建立阻碍了 HIV-1 的治愈， 让儿童终生受益的艺术。 PAVE 合作实验室的使命是利用尖端科学 建立对儿科 HIV-1 病毒库免疫发病机制的深入而广泛的了解 年龄范围，并证明临床前安全性和新疗法根除病毒库的有效性 和控制反弹，这将为未来的介入性人体研究铺平道路，以实现终生持续的研究 HIV-1 控制关闭 ART。我们假设婴儿免疫系统在婴儿时期的独特特征 储存库的建立影响病毒的长期持久性、对免疫的易感性等特征 介导的清除和重新激活与成人感染不同，需要深入研究 告知适合儿童的治疗方法。我们将测试这个假设并执行 PAVE Scientific 通过实现以下具体目标来制定议程： 1. 定义 围产期感染中的艾滋病毒潜伏库。 2、增强小儿免疫力，广泛中和 抗体 (bNAb) 递送以实现 ART 治疗后 HIV-1 的控制。 3. 部署免疫靶向 消除病毒储存库的策略。 4. 优化病毒学、免疫学和成像方法 评估 HIV-1/S(H)IV 治疗干预措施的功效。 5. 促进社区参与儿童艾滋病毒防治 治愈研究。 PAVE 项目是多学科、多文化、迭代且结构灵活的项目 由四个高度协同的研究焦点和国内和国际社区计划组成 这将迅速纳入新的科学方向和利益相关者的反馈。 PAVE 领导层 团队涵盖不同的科学专业知识，并在性别、学术排名和 原产地。每个研究焦点还包括初级教职人员共同研究人员，以促进他们的职业生涯 HIV-1研究领域的发展。通过我们科学领导层的集体努力， 执行委员会、科学顾问委员会、研究人员、行业合作伙伴、网络合作以及 PAVE 预计将在国内和国际社区计划中实现以下总体里程碑： 1）了解早期生命免疫和早期抗逆转录病毒治疗对病毒成分和稳定性的影响 潜在储存库，包括幼稚 T 细胞，以及 HIV-1 缓解的潜力； 2）消除这些水库 免疫靶向策略的临床前研究； 3) 定义骨髓细胞在 HIV-1 持续存在中的作用和 反弹，包括中枢神经系统； 4）建立通过积极增强儿童免疫力的新方法 和被动免疫； 5) 开发量化和监测原病毒库的尖端方法 衡量临床试验效果，以及 6) 促进社区积极参与儿科 HIV-1 治愈研究。 这些里程碑将有助于实现在儿科中持续无 ART 控制 HIV-1 复制的愿景 人口。