Pediatric Adolescent Virus Elimination (PAVE) Martin Delaney Collaboratory

摘要 在静息记忆CD 4 + T细胞中立即建立潜伏的HIV-1储库排除了HIV-1治愈， 在儿童中进行终生的强制性艺术治疗。PAVE合作实验室的使命是利用尖端科学 建立一个深入和广泛的了解免疫发病机制的儿科艾滋病毒-1水库，跨越 年龄谱，并证明根除储库的新型治疗剂的临床前安全性和有效性 并控制反弹，这将为未来的干预性人类研究铺平道路， 我们假设婴儿免疫系统的独特特征在婴儿出生时， 水库的建立影响了病毒的长期持续性、免疫易感性、 介导的清除和再激活，这是不同于成人感染， 告知适合儿童治疗疗法。我们将测试这一假设，并执行PAVE科学 通过实现以下具体目标实现议程：1.定义的建立和演变 围产期感染HIV潜伏宿主。2.增强小儿免疫力，广泛中和 抗体（bNAb）递送以实现HIV-1的治疗后控制脱离ART。部署免疫靶向 消除病毒宿主的策略。4.优化病毒学、免疫学和成像方法， 评估HIV-1/S（H）IV治愈干预措施的有效性。5.促进社区参与儿科艾滋病毒 治愈研究PAVE计划是多学科，多文化和迭代的灵活结构 由四个高度协同的研究重点和一个国内和国际社区计划所涵盖 这将迅速纳入新的科学方向和我们利益攸关方的反馈。PAVE领导层 团队跨越不同的科学专业知识，并在性别，学术级别和 原产国。每个研究重点还包括初级教师合作研究者，以促进他们的职业生涯 在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 国内和国际社区计划，PAVE预计满足以下总体里程碑： 1)了解生命早期免疫力和早期抗逆转录病毒治疗对抗逆转录病毒药物的组成和稳定性的影响， 潜伏的储库，包括在幼稚T细胞中，以及HIV-1缓解的潜力; 2）消除这些储库， 免疫靶向策略的临床前研究; 3）确定骨髓细胞在HIV-1持续存在中的作用， 反弹，包括在中枢神经系统; 4）建立新的方法，以提高小儿免疫力，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水库， 衡量临床试验的有效性，以及6）促进社区积极参与儿科HIV-1治疗研究。 这些里程碑将有助于实现在儿童中持续无ART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.