REACH: Research Enterprise to Advance a Cure for HIV

项目摘要/摘要 尽管标准的抗逆转录病毒疗法(ART)取得了成功，但对艾滋病毒治愈的需求仍然令人信服，两者 以改善威尔斯亲王医院的生活，并结束大流行。治疗艾滋病毒的策略属于 有两类：一类是寻求不含抗逆转录病毒药物的“缓解”，另一类是寻求经典疗法或“根除”。而当 这两种情况都有先例，后者只有通过骨髓移植才能实现。在……里面 相比之下，尽管自然发生的免疫介导的艾滋病毒控制(缓解)相对罕见，但许多这样的 已经描述了一些案例。我们提出的“马丁·德莱尼艾滋病毒治疗研究合作实验室”计划是 题为“REACH”--推进艾滋病毒治疗的研究企业。REACH的中心主题是蜂窝 免疫反应(NK和T细胞)与下一代病毒中和生物制剂相结合，可以 被利用来实现持久缓解和根除艾滋病毒携带者。拟议的研究重点是 缩小我们对我们试图扰乱的系统的基本原理的理解上的差距，即：艾滋病毒 与细胞免疫有关的蓄水池，作为实现有效和可行的艾滋病毒的真正进展的手段 治愈策略。我们的方法围绕三个研究重点，强调回到基础科学，但 将这一点与发现联系起来，指向缓解和根除的翻译管道。这个 拟议的目标，广义地定义，旨在：(1)重新定义持久性艾滋病毒之间的三向关系 蓄水池、CD8+T细胞和反弹病毒在单细胞、个体和不同群体水平上，(2) 利用常规和非常规(bNAb诱导的)CD8+T细胞反应，与bNAbs结合 和下一代生物制剂，以实现对艾滋病毒复制的持久控制，以及(3)开发一种从发现到 翻译流水线，以克服CTL/NK细胞根除艾滋病毒宿主的多重障碍。这些 研究将植根于强大的基础科学计划，该计划将把结果与新的洞察力联系起来 免疫介导库消除的障碍，包括前病毒整合部位的作用和病毒和 影响免疫易感性的宿主因素。我们的计划优先考虑对不同人群的研究，包括 感染非B亚型病毒的非洲人口和妇女--这两者都是为了朝着治愈所有人的方向前进，以及 从不同的视角中获益，以此作为基本见解的来源。这些目标将通过一个 由具有不同专业知识和强大合作历史的资深调查人员组成的小组，以及 社区和行业合作伙伴。

PROJECT SUMMARY/ABSTRACT Despite the success of standard antiretroviral therapy (ART), the need for an HIV cure remains compelling, both to improve the lives of PWH and to bring about the end of the pandemic. Strategies for an HIV cure fall under two categories: those that seek ART-free ‘remission’, and those targeting a classical cure or ‘eradication’. While precedents exist for both scenarios, the latter have only been achieved with bone marrow transplantation. In contrast, although naturally occurring immune-mediated control of HIV (remission) is relatively rare, many such cases have been described. Our proposed “Martin Delaney Collaboratory for HIV Cure Research” program is entitled “REACH” - Research Enterprise to Advance a Cure for HIV. The central theme of REACH is that cellular immune responses (NK and T-cells), combined with next generation virus-neutralizing biologics, can be harnessed to achieve durable remission and eradication of HIV reservoirs. The proposed research focuses on closing gaps in our understanding of the fundamentals of the system that we are trying to perturb, i.e.: the HIV reservoir in relation to cellular immunity, as the means to achieve real progress towards effective and viable HIV cure strategies. Our approach centers around three research foci, which emphasize back to basics science, but connect this with discovery to translational pipelines directed towards both remission and eradication. The proposed objectives, broadly defined, aim to: (1) redefine the three-way relationship between the persistent HIV reservoir, CD8+ T-cells, and rebound virus at the levels of: single cells, individuals, and diverse populations, (2) harness conventional and unconventional (bNAb-induced) CD8+ T-cells responses, in combination with bNAbs and ‘next generation’ biologics, to achieve durable control of HIV replication, and (3) develop a discovery-to- translation pipeline to overcome multiple barriers to the eradication of HIV reservoirs by CTL/NK cells. These studies will be rooted in a strong basic science program that will contextualize results with novel insights into barriers to immune-mediated reservoir elimination, including the role of the proviral integration site and of viral and host factors influencing immune susceptibility. Our program prioritizes the study of diverse populations, including African populations infected with non-B subtype virus, and women – both to advance towards a cure for all, and to benefit from diverse perspectives as a source of fundamental insights. These objectives will be realized by a group of accomplished investigators of diverse expertise and with strong collaborative histories, along with community and industry partners.