I4C 2.0: Immunotherapy for Cure

总结 I4 C 2.0的目标是促进我们对病毒库的科学理解，并开发免疫学 通过高度协作和多方面的研究计划缓解和根除HIV-1的战略 涉及学术界、工业界、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ART- 免费病毒学控制或完全病毒根除，目的是选择联合治疗方案， 在拟定的支持期结束前进入临床开发阶段。我们提出了三 研究重点，管理和业务科，以及社区参与科。 焦点1（储库靶向和病毒持久性的机制基础） 目标1.定义病毒持久性和反弹的病毒学、免疫学和转录组学特征， 确定免疫策略如何靶向NHP和人类中的病毒储库 目标二。确定NHP中具有复制能力的病毒库的克隆扩增和持久性的驱动因素 和人类来加强水库控制和消除 焦点2（持续缓解病毒的新策略） 目标1.评估创新的免疫工程策略，提供长期的T细胞或Env导向的 免疫控制，包括治疗性疫苗、CAR-T细胞和工程化B细胞 目标2.联合收割机的方法，增强体液和细胞免疫反应，以实现持续 免疫监视和长期无ART病毒学控制 焦点3（病毒根除的新策略） 目标1。评价快速消除大部分病毒储库的创新策略，包括 与bNAb、活化NK细胞和CAR-T细胞联合的改良LRA 目标二。为了将快速消除大部分病毒宿主的最有效方法联合收割机与 持续的免疫监测，以消除残留的病毒储存库 管理及运作组 社区参与组

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