Pediatric Adolescent Virus Elimination (PAVE) Martin Delaney Collaboratory

摘要 在静止记忆的CD4+T细胞中立即建立潜伏的HIV-1储存库就排除了HIV-1的治愈， 令人信服的儿童一生的艺术。Pave合作实验室的使命是使用尖端科学 建立对儿童HIV-1宿主免疫发病机制的深入而广泛的了解 年龄谱，并展示根除水库的新疗法的临床前安全性和有效性 和控制反弹，这将为未来的介入性人体研究铺平道路，走向终身持续的 抗逆转录病毒药物治疗对HIV-1病毒的控制。我们假设当时婴儿免疫系统的独特特征 水库的建立影响了病毒的长期持久性、免疫易感性等特点。 与成人感染不同的中介清除和重新激活，值得深入调查 告知适合儿童的治疗方法。我们将检验这一假设并执行Pave Science 议程通过实现以下具体目标来实现：1.界定 HIV在围产期感染中的潜伏库。2.增强儿科免疫力，广泛中和 抗体(BNAb)传递，实现治疗后控制HIV-1脱离ART。3.部署免疫靶向 消除病毒库的策略。4.优化病毒学、免疫学和成像方法以 评估HIV-1/S(H)IV治愈干预措施的效果。5.促进社区对儿童艾滋病毒的参与 治愈研究。Pave项目是多学科、多文化的，具有灵活的结构和迭代 由四个高度协同的研究中心和一个国内和国际社区计划组成 这将迅速纳入新的科学方向和我们利益相关者的反馈。铺路领导层 团队跨越了不同的科学专业知识，并在性别、学术级别和 原产国。每个研究中心还包括初级教员联合调查员，以促进他们的职业生涯 在艾滋病毒-1研究领域内的发展。通过我们科学领导层的集体努力， 执行委员会、科学咨询委员会、调查人员、行业合作伙伴、网络协作和 国内和国际社区计划，Pave预计将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的组成和稳定性的影响 潜伏性储存，包括在幼稚T细胞中，以及艾滋病毒-1缓解的可能性；2)消除这些储存 免疫靶向策略的临床前研究；3)确定髓系细胞在HIV-1持续和 反弹，包括在中枢神经系统；4)建立新的方法，通过积极的 和被动免疫；5)开发尖端方法来量化和监测前病毒宿主，以 评估临床试验的有效性，以及6)促进社区积极参与儿童HIV-1治疗研究。 这些里程碑将有助于实现在儿科患者中持续无抗逆转录病毒疗法控制HIV-1复制的愿景 人口。

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.