Reversing Immune Dysfunction for HIV-1 Eradication

逆转免疫功能障碍以根除 HIV-1

• 批准号: 10469447
• 负责人: SUMIT K CHANDA
• 金额: $ 498.68万
• 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/10469447
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Age; Allogenic; Anatomy; Antibodies; Automobile Driving; B-Lymphocytes; BCL1 Oncogene; Binding; 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; HIV/AIDS; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunology; Immunomodulators; Individual; Infection; Infrastructure; Innate Immune Response; Institution; Interruption; Intervention; Investments; Knowledge; Laboratory Research; Ligands; Maintenance; Mediating; Metabolic Control; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Outcome; Outcome Study; Pathway interactions; Patients; 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; cohort; collaboratory; design; drug repurposing; experience; gut microbiome; high risk; immune function; immune restorative treatment; 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; pharmacologic; pre-clinical; preservation; prevent; receptor; recruit; 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之一。 就是需要恢复正常的免疫功能，才能有效消除已经建立的病毒库。 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” 此外，默克还拥有病毒学、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。 研究实验室将投入大量的智力、人力和物力资源来补充 RID-HIV 合作实验室将共同努力探索其根本原因。 HIV感染者免疫失调的基础及其对储存库持续性的影响 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 RID-HIV 合作实验室的总体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 增强病毒再激活和消除策略，以实现 HIV-1 治愈，我们提出了三个高度的建议。 综合和互补的科学研究焦点（RF），由严格和迭代模型支持 在 RF1 中，我们将研究其机制。 因此，宿主和微生物组衍生的代谢物会影响先天免疫反应并影响 在 RF2 中，我们将追求以下假设：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 此外，在治疗中断后，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 在 RF 3 中，我们将优化这种新型细胞治疗产品的功能。 剂（LRA）并识别具有协同 LRA 活性的临床阶段分子，以清除重新激活的细胞。 使用一种新的 NK 细胞招募策略和通过基因改造 B 细胞以产生 最后，基因编辑将被部署用于增强病毒库清除能力的广泛中和 HIV-1 抗体。 RF1、RF2 中不适合 LRA 的体内靶向和消除潜伏原病毒。 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。

项目成果

Opportunities for CAR-T Cell Immunotherapy in HIV Cure.

CAR-T 细胞免疫疗法在 HIV 治疗中的机会。

• 发表时间: 2023-03-19
• 作者: Campos;Martinez;Velasco;Salgado, Maria
• 通讯作者: Salgado, Maria

Role of Siglecs in viral infections: A double-edged sword interaction.

Siglecs 在病毒感染中的作用：双刃剑相互作用。

• 发表时间: 2023-04
• 影响因子: 10.6
• 作者: Raïch;Resa;Gallemí, Marçal;Laguia, Fernando;Muñiz;Muñoz;Perez;Chojnacki, Jakub;Benet, Susana;Clotet, Bonaventura;Martinez;Izquierdo
• 通讯作者: Izquierdo

Altered T-cell subset distribution in the viral reservoir in HIV-1-infected individuals with extremely low proviral DNA (LoViReTs).

前病毒 DNA (LoViReTs) 极低的 HIV-1 感染者的病毒库中 T 细胞亚群分布发生改变。

• 发表时间: 2022-08
• 影响因子: 11.1
• 作者: Gálvez, Cristina;Urrea, Víctor;Garcia;Bernal, Sílvia;Benet, Susana;Mothe, Beatriz;Bailón, Lucía;Dalmau, Judith;Martinez, Andrea;Nieto, Aroa;Leal, Lorna;García, Felipe;Clotet, Bonaventura;Martinez;Sal
• 通讯作者: Sal

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure.

打破沉默：治愈之路上艾滋病毒转录和潜伏期的调节。

• 发表时间: 2023-12-15
• 作者: Duggan, Natasha N;Dragic, Tatjana;Chanda, Sumit K;Pache, Lars
• 通讯作者: Pache, Lars

Regulation of Immune Homeostasis, Inflammation, and HIV Persistence by the Microbiome, Short-Chain Fatty Acids, and Bile Acids.

微生物组、短链脂肪酸和胆汁酸对免疫稳态、炎症和 HIV 持续性的调节。

• DOI: 10.1146/annurev-virology-040323-082822
• 发表时间: 2023-09-29
• 期刊: Annual review of virology
• 作者: Ana Beatriz Enriquez;Felipe Ten Caten;K. Ghneim;R. Sékaly;Ashish Arunkumar Sharma
• 通讯作者: Ashish Arunkumar Sharma