Reversing Immune Dysfunction for HIV-1 Eradication

项目摘要 虽然新的艾滋病毒感染率有所下降，但遏制和最终根除艾滋病毒仍然是一个挑战。 大流行病仍然是当代生物医学研究的首要任务。艾滋病治疗的主要挑战之一 需要恢复正常的免疫功能，以便有效地消除已建立的病毒储存库。我们 在RID-HIV：“逆转免疫功能障碍以根除HIV-1”中，基础和临床科学家聚集在一起， 在病毒学、免疫学、微生物组生物学、表观遗传学和系统生物学方面具有专长。此外，Merck 研究实验室将投入大量的智力、人力和物力资源， 学术科学家的努力。RID-HIV合作实验室将共同探讨 艾滋病毒感染者免疫失调的基础及其对宿主持久性的影响， 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 由微生物组和宿主以及细菌代谢组印记的机制， 有效的先天性和适应性免疫反应，可以控制大小，质量和解剖定位 艾滋病病毒的储存库。RID-HIV合作实验室的首要目标是提供临床前体内证据， 治疗范例的概念，包括免疫恢复治疗，与 增强病毒再激活和消除策略，以提供HIV-1治愈。我们提出三个高度 综合和互补的科学研究重点（RF），由严格和迭代建模支持 我们的目标是通过我们对艾滋病毒社区的宣传来实现。在RF 1中，我们将研究 由此宿主和微生物组衍生的代谢物影响先天免疫应答并影响免疫应答。 维持潜伏的病毒库。在RF 2中，我们将继续假设在ART/ATI临床队列中， 控制先天免疫的代谢物形成了可以防止病毒反弹的适应性免疫反应 治疗中断时。此外，我们将评估工程化同种异体干记忆T细胞的能力， 细胞提供上级同源帮助促进抗病毒CD 8 T细胞的效应子功能，并将评估 FDA批准的新型免疫调节剂重置这种基线免疫功能障碍的能力， 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 试剂（LRA）和鉴定具有协同LRA活性的临床阶段分子。清除重新激活的细胞将 使用NK细胞募集的新策略和通过遗传修饰B细胞以产生 广泛中和HIV-1抗体，增强储库清除。最后，基因编辑将被部署用于 体内靶向和消除对LRA不敏感的潜伏前病毒。RF 1、RF 2中的研究结果 和RF 3将能够合成预测数学模型，以建立最可能的组合 这些疗法将在一个旨在建立概念验证的顶点进行测试， 在NHP模型中使用这些策略，并将其转化为临床。

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.