Reversing Immune Dysfunction for HIV-1 Eradication

逆转免疫功能障碍以根除 HIV-1

• 批准号: 10540209
• 负责人: SUMIT K CHANDA
• 金额: $ 498.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540209
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; Age; Allogenic; Anatomy; Antibodies; 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; 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

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.

项目概要 尽管新发艾滋病毒感染率有所下降，但艾滋病毒的遏制和最终根除仍 大流行仍然是当代生物医学研究的首要任务。艾滋病毒治愈的主要挑战之一 是需要恢复正常的免疫功能，才能有效消除已建立的病毒库。我们 基础科学家和临床科学家在 RID-HIV 中集结：“逆转免疫功能障碍，根除 HIV-1” 拥有病毒学、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。此外，默克 研究实验室将投入大量的智力、人力和物力资源来补充 学术界科学家的努力。 RID-HIV 合作实验室将共同探索潜在的问题 HIV感染者免疫失调的基础及其对储存库持续性的影响 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、宿主和细菌代谢组印记的阻止发育的机制 有效的先天和适应性免疫反应，可以控制大小、质量和解剖定位 HIV 储存库。 RID-HIV 合作实验室的首要目标是提供临床前体内证据- 治疗范式的概念，包括免疫恢复治疗，与 加强病毒再激活和消除策略，以实现 HIV-1 治愈。我们高度推荐三点 综合和互补的科学研究焦点（RF），由严格和迭代模型支持 的成果，并由我们对艾滋病毒社区的外展活动决定。在 RF1 中我们将研究其机制 由此宿主和微生物组衍生的代谢物影响先天免疫反应并影响 维持潜伏病毒库。在 RF2 中，我们将追求这样的假设：在 ART/ATI 临床队列中， 控制先天免疫的代谢物塑造适应性免疫反应，从而防止病毒反弹 治疗中断后。此外，我们将评估工程同种异体干记忆T的能力 细胞提供卓越的同源帮助，促进抗病毒 CD8 T 细胞的效应功能，并将评估 FDA 批准的新型免疫调节剂能够重置这种基线免疫功能障碍，并且 增强这种新型细胞治疗产品的功能。在 RF 3 中，我们将优化一流的延迟反转 剂（LRA）并识别具有协同 LRA 活性的临床阶段分子。清除重新激活的细胞将 使用一种新的 NK 细胞招募策略和通过基因改造 B 细胞来增强 广泛中和 HIV-1 抗体，增强储库清除能力。最后，基因编辑将被部署用于 体内靶向和消除不适合 LRA 的潜伏原病毒。 RF1、RF2的研究结果 RF3 将能够综合预测数学模型来建立最可能的组合 实现 HIV-1 治愈的疗法，并将在最终目标中进行测试，以建立概念验证 在 NHP 模型中应用这些策略，并将其转化为临床。