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

多组学鉴定和验证免疫干预触发的机制，旨在减少复制能力储库的大小

• 批准号: 10731661
• 负责人: Rafick Pierre Sekaly
• 金额: $ 129.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731661
• 关键词: Adaptive Immune System; Agonist; Allogenic; Anti-Retroviral Agents; Antibodies; Antigens; Autologous; B-Lymphocytes; Binding; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Chimerism; Circulation; Clinic; Collaborations; Data Set; Dedications; Detection; Disease; Effector Cell; Engraftment; Environment; Flow Cytometry; Future; Gene Silencing; Goals; HIV; HIV Infections; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Human immunodeficiency virus test; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunologics; Immunology; Immunotherapy; Impairment; Individual; Inflammatory; Infusion procedures; Innate Immune Response; Innate Immune System; Interruption; Intervention; Machine Learning; Macrophage; Malignant Neoplasms; Mediating; Modality; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mutation; Nature; PD-1 blockade; PD-1/PD-L1; Participant; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Positioning Attribute; Recording of previous events; Refractory; Role; Sampling; Signal Transduction; Systems Biology; T cell response; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Vaccines; Validation; Viral; Viremia; Virus; acute infection; adaptive immune response; anti-PD-1; anti-PD-L1; antiretroviral therapy; arm; cell killing; clinical efficacy; cohort; cytokine; cytotoxicity; data integration; experimental study; host microbiome; immune activation; immune activator; immune function; immune reconstitution; immunological intervention; immunoregulation; improved; improved outcome; metabolome; metabolomics; microbial; microbiome; monocyte; multidimensional data; multiple omics; network models; neutralizing antibody; novel; novel therapeutics; prevent; programs; response; stem; success; synergism; targeted treatment; therapeutic vaccine; viral rebound; virology

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.

尽管有有效控制血浆病毒血症的抗逆转录病毒（ART）药物，但艾滋病毒库池抑制了潜在感染的细胞 形成一个持续的储层，可防止对病毒感染细胞的清除。停止艺术治疗后， 即使在急性感染期间开始启动ART，该储层会导致血浆病毒血症的快速反弹。 根除或永久沉默的储层是许多HIV治疗策略的重点。免疫功能障碍 包括受损的T细胞反应是HIV疾病的标志。免疫指导的治疗策略寻求 克服这种失调以恢复正常的免疫功能并促进艾滋病毒感染细胞的杀死。这 迄今为止，基于免疫的治疗策略的临床功效有限，表明还可以恢复更多 免疫功能比靶向T和B细胞。我们假设治愈激活和 恢复正常的先天和适应性免疫功能将更有效地减少艾滋病毒库，并 限制停止艺术后的病毒反弹。为了检验这一假设，我们将采用广泛的多摩变 由病毒学，免疫学和分子测定的平台来定义同时重新的作用 通过3种不同的治疗艾滋病毒动力学的策略来对先天和适应性免疫系统进行启发 并在中止艺术后的病毒反弹。第一个策略（项目1）将调查如何与 Lefitolimod（先天免疫TLR9激动剂）和广泛中和抗体促进了HIV的清除 通过启动先天免疫反应并使用FC-提供靶向感染细胞的抗体，储存库 介导的先天免疫效应子功能。第二个策略（项目2）将测试PD-的封锁 通过单克隆抗体治疗1/PD-L1信号轴可增强炎症单核细胞/巨噬细胞 响应并恢复CD4和CD8 T细胞功能。第三个策略（项目3）将研究植入 与表达CCR5D32突变或自体输注CCR5的同种异体造血干细胞 删除的CD4+ T细胞用功能效应细胞重新填充免疫室，这些细胞对HIV难治性 感染导致杀死艾滋病毒的水库，缺乏病毒反弹。对于所有项目，我们将定义如何 宿主和微生物代谢产生的宿主环境差异调节免疫学 确定的机制可以介导HIV储层清除和/或限制病毒反弹。结果分析 将通过专用的机器学习和建模核心执行。这个核心最终将负责 用于生成集成的多摩变网络模型，该模型可以预测微生物组/代谢物特征 直接调节与HIV储层或病毒反弹减少相关的免疫机制； 在每个队列/项目中乃至整个项目中都可以确定多种策略的共同特征。我们的团队 专家的合作广泛，并且在完成该计划的目标方面处于独特状态。