Reversing Immune Dysfunction for HIV-1 Eradication

逆转免疫功能障碍以根除 HIV-1

基本信息

批准号：
10313784
负责人：
SUMIT K CHANDA
金额：
$ 500.18万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313784
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Adult Age Allogenic Anatomy Antibodies Antiviral Agents Automobile Driving B-Lymphocytes BCL2 gene Biology Biomedical Research CCR5 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Therapy Cell physiology Cells Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Combined Modality Therapy Communities Community Outreach Complement Containment Development Effector Cell Engineering Engraftment Ensure Epigenetic Process FDA approved FRAP1 gene Feedback Future Genes Genetic Goals HIV HIV Infections HIV-1 Homeostasis Human Immune Immune System Diseases Immune response Immune system Immunology Immunomodulators Individual Infection Infrastructure Innate Immune Response Institution Interruption Intervention Knowledge Laboratory Research Ligands Maintenance Mediating Metabolic Control Modeling Molecular Morbidity - disease rate Natural Immunity Natural Killer Cells Outcome Outcome Study Pathway interactions Patients Pharmacology Proviruses Reagent Recording of previous events Research Resources Scientist Shapes Systems Biology T memory cell T-Lymphocyte Testing Therapeutic Time Transforming Growth Factor beta Translations Tumor Debulking Universities Viral Viral reservoir Virus Virus Latency Virus Replication Voice Work adaptive immune response antiretroviral therapy base cohort collaboratory design drug repurposing experience gut microbiome high risk host microbiome immune function imprint improved outcome in vivo in vivo evaluation inhibitor/antagonist innovation latent HIV reservoir mathematical model member metabolome microbiome monocyte mortality neutralizing antibody neutrophil novel novel strategies novel therapeutic intervention outreach pandemic disease pre-clinical preservation prevent receptor recruit restorative treatment stem success therapy adherence tool viral rebound virology

项目摘要

PROJECT SUMMARY Although the rate of new HIV infections has decreased, containment and eventual eradication of the HIV pandemic remains a top priority in contemporary biomedical research. One of the major challenges to HIV cure is the need to restore normal immune function in order to effectively eliminate the established viral reservoir. We have assembled in RID-HIV: “Reversing Immune Dysfunction for HIV-1 eradication”, basic and clinical scientists with expertise in virology, immunology, microbiome biology, epigenetics, and systems biology. In addition, Merck Research Laboratories will invest significant intellectual, human and material resources to complement the efforts of the academic scientists. The RID-HIV Collaboratory will collectively function to explore the underlying basis of the immune dysregulation in HIV-infected individuals and the impact it has on reservoir persistence and viral rebound control. We will test for the first time several innovative concepts, including identifying epigenetic mechanisms imprinted by the microbiome and host and bacterial metabolomes that prevents the development of effective innate and adaptive immune responses that can control the size, quality and anatomical localization of the HIV reservoir. The overarching goal of the RID-HIV Collaboratory is to provide preclinical in vivo proof-of- concept for a therapeutic paradigm that encompasses immune restorative treatments, used in concert with enhanced viral reactivation and elimination strategies, in order to deliver a HIV-1 cure. We propose three highly integrated and complementary scientific Research Foci (RFs), to be supported by rigorous and iterative modeling of outcomes and shaped by our outreach to the HIV community. In RF1 we will investigate the mechanisms whereby host- and microbiome-derived metabolites impact innate immune responses and influence the maintenance of the latent viral reservoir. In RF2 we will pursue the hypothesis that in ART/ATI clinical cohorts, metabolites that govern innate immunity shape the adaptive immune responses that could prevent viral rebound upon treatment interruption. In addition, we will evaluate the capacity of engineered allogenic stem memory T cells to provide superior cognate help to promote the effector functions of antiviral CD8 T cells, and will assess the ability of FDA-approved and novel immune modulators to reset this baseline immune dysfunction and enhance the function of this novel cell therapy product. In RF 3 we will optimize a best-in-class latency reversal agent (LRA) and identify clinical-stage molecules with synergistic LRA activity. Clearance of reactivated cells will be enhanced using a novel strategy for NK cell recruitment and by genetically modifying B cells to produce broadly neutralizing HIV-1 antibodies that enhance reservoir clearance. Finally, gene editing will be deployed for in vivo targeting and elimination of latent provirus not amenable to LRAs. The outcomes of studies in RF1, RF2 and RF3 will enable the synthesis of a predictive mathematical model to establish the most likely combinations of therapies to achieve an HIV-1 cure, and which will be tested in a capstone aim to establish proof-of-concept for these strategies in NHP models and to enable translation to the clinic.

项目摘要尽管新的艾滋病毒感染的发生率恶化了，但遏制和消除了艾滋病毒的事件大流行仍然是当代生物医学研究的重中之重。艾滋病毒治愈的主要挑战之一是否需要恢复正常的免疫功能以有效消除已建立的病毒储存库。我们在Rid-HIV中组装：“消除HIV-1的免疫功能障碍”，基本和临床科学家具有病毒学，免疫学，微生物组生物学，表观遗传学和系统生物学方面的专业知识。另外，默克研究实验室将投资大量的智力，人力和物质资源来完成学术科学家的努力。 RID-HIV协作将共同发挥作用来探索基础艾滋病毒感染者的免疫失调及其对水库持久性的影响和病毒反弹控制。我们将首次测试几个创新概念，包括识别表观遗传微生物组，宿主和细菌代谢组烙印的机制可防止发展可以控制大小，质量和解剖学定位的有效先天和适应性免疫复杂艾滋病毒水库。 RID-HIV合作的总体目标是提供体内临床前 - 用于涵盖免疫修复治疗的治疗范式的概念，与为了提供HIV-1治疗，增强了病毒重新激活和消除策略。我们提出了三个综合和互补的科学研究焦点（RFS），由严格且迭代的建模支持结果，并由我们与艾滋病毒社区的宣传所塑造。在RF1中，我们将研究机制宿主和微生物组衍生的代谢产物影响先天免疫反应并影响维护潜在病毒储存库。在RF2中，我们将提出以下假设：在ART/ATI临床队列中，管理先天免疫的代谢产物可以防止病毒反弹的适应性免疫复杂治疗中断。此外，我们将评估工程纯粹的茎记忆的能力t 细胞提供优质的同源有助于促进抗病毒CD8 T细胞的效应子功能，并将评估 FDA批准和新型免疫调节剂重置此基线免疫功能障碍的能力和增强这种新型细胞疗法的功能。在RF 3中，我们将优化一流的延迟逆转代理（LRA）并鉴定具有协同LRA活性的临床阶段分子。重新激活的细胞的清除将使用新的NK细胞募集策略并通过基因修饰B细胞来增强广泛中和HIV-1抗体，可增强储层清除率。最后，将部署基因编辑在体内靶向和消除LRA不适合的潜在病毒。 RF1，RF2的研究结果 RF3将使预测数学模型的合成能够建立最可能的组合实现HIV-1治疗的疗法，并将在盖石旨在建立概念证明的目标中进行测试对于NHP模型中的这些策略，并可以翻译为诊所。