I4C 2.0: Immunotherapy for Cure

摘要 I4C2.0的目标是促进我们对病毒库的科学理解，并发展免疫学 通过高度协作和多方面的研究计划缓解和根除艾滋病毒-1的战略 涉及学术界、产业界、政府和社区之间的伙伴关系。我们的总体假设是 需要探索和结合多种免疫策略，以实现长期的、抗逆转录病毒治疗- 免费病毒学控制或完全根除病毒，目标是选择联合方案来 在拟议的支持期结束前进入临床开发阶段。我们提出三个建议 研究中心，一个管理和运营科，以及一个社区参与科。 焦点1(水库靶向和病毒持久性的机理基础) 目的1.定义病毒持续和反弹的病毒学、免疫学和转录学特征，并 确定免疫策略如何针对NHP和人类中的病毒库 目的2.确定NHP中具有复制能力的病毒库的克隆性扩张和持久性的驱动因素 和人类加强对水库的控制和消除 焦点2(病毒持续缓解的新策略) 目的1.评估提供长期T细胞或环境导向的创新免疫工程策略 免疫控制，包括治疗性疫苗、CAR-T细胞和工程B细胞 目标2.结合增强体液和细胞免疫反应的方法以实现持续 免疫监测和长期无ART病毒学控制 Focus 3(新的病毒根除策略) 目的1.评估迅速消灭大多数病毒库的创新战略，包括 改进的LRAs结合bNAbs、激活的NK细胞和CAR-T细胞 目标2.结合最有效的方法来快速消除大多数病毒库和 持续免疫监测消除残留病毒库 管理和业务(业务)科 社区参与(CE)组

SUMMARY The goals of I4C 2.0 are to advance our scientific understanding of the viral reservoir and to develop immunologic strategies for HIV-1 remission and eradication by a highly collaborative and multifaceted research program involving partnerships among academia, industry, government, and the community. Our overall hypothesis is that multiple immunologic strategies will need to be explored and combined to achieve long-term, ART- free virologic control or complete virus eradication, with the goal of selecting combination regimens to advance into clinical development by the end of the proposed period of support. We propose three Research Foci, a Management and Operations Section, and a Community Engagement Section. Focus 1 (Mechanistic Basis of Reservoir Targeting and Viral Persistence) Aim 1. To define a virologic, immunologic, and transcriptomic signature of viral persistence and rebound and to determine how immunologic strategies target the viral reservoir in NHPs and humans Aim 2. To define drivers of clonal expansion and persistence of the replication-competent viral reservoir in NHPs and humans to enhance reservoir control and elimination Focus 2 (Novel Strategies for Sustained Virus Remission) Aim 1. To evaluate innovative immune engineering strategies that provide long-term T cell or Env-directed immune control, including therapeutic vaccines, CAR-T cells, and engineered B cells Aim 2. To combine approaches that augment humoral and cellular immune responses to achieve sustained immunosurveillance and long-term ART-free virologic control Focus 3 (Novel Strategies for Virus Eradication) Aim 1. To evaluate innovative strategies for rapid elimination of the majority of the viral reservoir, including improved LRAs combined with bNAbs, activated NK cells, and CAR-T cells Aim 2. To combine the most effective approach to rapidly eliminate the majority of the viral reservoir with sustained immunosurveillance to eliminate the residual viral reservoir Management and Operations (MO) Section Community Engagement (CE) Section