Multi-OMICS identification and validation of mechanisms triggered by Immune interventions aimed at reducing the size of the replication competent Reservoir

尽管抗逆转录病毒 (ART) 药物可以有效控制血浆病毒血症，但仍有大量 HIV 潜伏感染细胞 形成持久的储存库，阻止病毒感染细胞的清除。停止 ART 治疗后， 即使在急性感染期间早期开始抗逆转录病毒治疗，这种病毒库也会导致血浆病毒血症迅速反弹。 根除或永久抑制该病毒库是许多艾滋病毒治疗策略的重点。免疫功能障碍 T 细胞反应受损是 HIV 疾病的一个标志。免疫定向治疗策略旨在 克服这种失调，恢复正常的免疫功能并促进杀死 HIV 感染细胞。的 迄今为止，基于免疫的治疗策略的临床疗效有限，这表明可能还有更多的方法可以恢复 免疫功能优于靶向 T 和 B 细胞。我们假设治愈策略可以激活和 恢复正常的先天性和适应性免疫功能将更有效地减少艾滋病毒储存和 限制 ART 停止后病毒反弹。为了检验这个假设，我们将采用广泛的多组学 由病毒学、免疫学和分子检测组成的平台，用于定义同时重新检测的作用 通过 3 种不同的 HIV 储存动态治疗策略来增强先天性和适应性免疫系统 以及停止 ART 后病毒反弹。第一个策略（项目 1）将研究如何与 Lefitolimod（先天免疫 TLR9 激动剂）和广泛中和抗体可促进 HIV 的清除 通过启动先天免疫反应并使用 Fc- 提供针对感染细胞的抗体来形成储存库 介导的先天免疫效应功能。第二个策略（项目 2）将测试如何封锁 PD- 单克隆抗体治疗的 1/PD-L1 信号轴导致炎症单核细胞/巨噬细胞增强 反应并恢复 CD4 和 CD8 T 细胞功能。第三个策略（项目 3）将研究如何植入 使用表达 CCR5D32 突变的同种异体造血干细胞或自体输注 CCR5 删除的 CD4 T 细胞用对 HIV 耐药的功能性效应细胞重新填充免疫区室 感染导致艾滋病毒储存库被杀死并且病毒不会反弹。对于所有项目，我们将定义如何 宿主和微生物代谢物引起的宿主环境差异调节免疫学 已确定介导 HIV 储存库清除和/或限制病毒反弹的机制。结果分析 将由专用的机器学习和建模核心执行。这个核心将最终负责 用于生成集成的多组学网络模型，预测微生物组/代谢物特征 直接调节与减少艾滋病毒储存或病毒反弹相关的免疫机制； 在每个队列/项目内以及跨项目以确定多个策略的共同特征。我们的团队 专家们进行了广泛的合作，并且具有独特的优势来完成该计划的目标。

In spite of antiretroviral (ART) drugs which effectively control plasma viremia, a pool of HIV latently infected cells form a persistent reservoir that prevents clearance of virally infected cells. Upon cessation of ART treatment, this reservoir leads to a rapid rebound in plasma viremia, even if ART is initiated early during acute infection. Eradicating or permanently silencing this reservoir is the focus of many HIV cure strategies. Immune dysfunction including impaired T cell responses are a hallmark of HIV disease. Immune directed cure strategies seek to overcome this dysregulation to restore normal immune function and promote killing of HIV infected cells. The limited clinical efficacy of immune-based cure strategies to date suggests that there may be more to restoring immune function than targeting T and B cells. We hypothesize that cure strategies which activate and restore normal innate and adaptive immune function will more effectively reduce the HIV reservoir and limit viral rebound after cessation of ART. To test this hypothesis, we will employ an expansive multi-Omic platform consisting of virological, immunological and molecular assays to define the role of simultaneous re- invigoration of the innate and adaptive immune systems by 3 distinct cure strategies on HIV reservoir dynamics and viral rebound after discontinuing ART. The first strategy (Project 1) will investigate how co-treatment with Lefitolimod (innate immune TLR9 agonist) and broadly neutralizing antibodies promotes clearance of the HIV reservoir by priming innate immune responses and providing the antibodies to target infected cells using Fc- mediated innate immune effector functions. The second strategy (Project 2) will test how blockade of the PD- 1/PD-L1 signaling axis by monoclonal antibody therapy leads to enhanced inflammatory monocyte/macrophage responses and restored CD4 and CD8 T cell function. The third strategy (Project 3) will study how engraftment with allogeneic hematopoietic stem cells expressing the CCR5D32 mutation or autologous infusion of CCR5 deleted CD4+ T cells repopulate the immune compartment with functional effector cells that are refractory to HIV infection leading to killing of the HIV reservoir and a lack of viral rebound. For all Projects, we will define how differences in the host environment resulting from host and microbial metabolites modulate the immunological mechanisms identified to mediate clearance of the HIV reservoir and/or limit viral rebound. Analysis of results will be performed by a dedicated Machine Learning and Modeling Core. This core will ultimately be responsible for generating integrated multi-Omic network models which predict the microbiome/metabolite features which directly regulate the immune mechanisms associated with reduction in either the HIV reservoir or viral rebound; both within each cohort/Project and across Projects to identify common features to multiple strategies. Our team of experts have collaborated extensively and are uniquely positioned to complete the goals of this program.