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，但一群HIV潜伏感染的细胞 形成一个持久的蓄水池，防止病毒感染细胞的清除。在停止抗逆转录病毒治疗后， 即使在急性感染早期启动抗逆转录病毒治疗，这种储存库也会导致血浆病毒血症的迅速反弹。 根除或永久消除这种蓄水池是许多艾滋病毒治疗策略的重点。免疫功能障碍 包括受损的T细胞反应是艾滋病毒疾病的一个标志。免疫导向治疗策略寻求 克服这种失调，以恢复正常的免疫功能，并促进对艾滋病毒感染细胞的杀伤。这个 到目前为止，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恢复 免疫功能优于靶向T和B细胞。我们假设激活和激活的治愈策略 恢复正常的先天免疫和获得性免疫功能将更有效地减少艾滋病毒的储存和 限制病毒在停止抗逆转录病毒治疗后反弹。为了验证这一假设，我们将使用一个扩展的多体 由病毒学、免疫学和分子检测组成的平台，以确定同时重组病毒的作用 三种不同的治疗策略对HIV储存库动态的强化作用 并在停止ART后病毒式反弹。第一个战略(项目1)将调查如何与 Lefitolimod(先天免疫TLR9激动剂)和广谱中和抗体促进HIV的清除 通过启动先天免疫反应并使用Fc-1提供针对受感染细胞的抗体 介导的先天免疫效应器功能。第二个战略(项目2)将测试如何封锁PD- 单抗治疗1/PD-L1信号轴导致炎性单核/巨噬细胞增强 并恢复CD4和CD8T细胞功能。第三个战略(项目3)将研究如何嫁接 表达CCR5D32突变的异基因造血干细胞或自体输注CCR5 被删除的CD4+T细胞用对HIV无效的功能效应细胞重新填充免疫隔间 感染导致艾滋病毒携带者死亡，病毒反弹不足。对于所有项目，我们将定义如何 宿主和微生物代谢产物引起的宿主环境差异调节免疫学 已确定的机制可调节艾滋病毒蓄积物的清除和/或限制病毒反弹。结果分析 将由专门的机器学习和建模核心执行。这个核心最终将对 用于生成预测微生物组/代谢物特征的集成多组学网络模型 直接调节与减少艾滋病毒储存或病毒反弹有关的免疫机制； 在每个队列/项目内和跨项目，以确定多个战略的共同特征。我们队 专家们进行了广泛的合作，并处于独特的地位，可以完成这一计划的目标。