Reversing Immune Dysfunction for HIV-1 Eradication

项目总结 尽管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 大流行仍然是当代生物医学研究的重中之重。治愈艾滋病毒的主要挑战之一 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 已经聚集在RID-HIV：“扭转免疫功能障碍，根除HIV-1”，基础和临床科学家 拥有病毒学、免疫学、微生物群生物学、表观遗传学和系统生物学方面的专业知识。此外，默克公司 研究实验室将投入大量的智力、人力和物力，以补充 学术科学家的努力。RID-HIV合作实验室将共同发挥作用，探索潜在的 HIV感染者免疫失调的基础及其对宿主持久性和 病毒反弹控制。我们将首次测试几个创新概念，包括识别表观遗传学 微生物组、宿主和细菌代谢物所印记的机制阻止了发育 有效的先天性和获得性免疫反应，可以控制大小、质量和解剖定位 艾滋病病毒携带者。RID-HIV合作实验室的首要目标是提供临床前的活体证明。 治疗范例的概念，包括免疫恢复性治疗，与 加强病毒重新激活和消除战略，以提供艾滋病毒-1治愈方法。我们提出三个高度的建议 综合和互补的科学研究重点(RFS)，得到严格和迭代建模的支持 结果的影响，以及我们对艾滋病毒社区的接触所塑造的。在RF1中，我们将研究这些机制 宿主和微生物组衍生的代谢物影响先天免疫反应并影响 维护潜伏的病毒库。在RF2中，我们将继续假设，在ART/ATI临床队列中， 支配先天免疫的代谢物塑造可防止病毒反弹的获得性免疫反应 在治疗中断时。此外，我们还将评估工程化同种异体干细胞记忆T细胞的能力 为细胞提供优越的同源帮助，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重置这一基线免疫功能障碍和 增强这一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)，并鉴定具有协同LRA活性的临床阶段分子。清除重新激活的细胞将 通过一种新的NK细胞募集策略和通过基因修饰B细胞来产生 广泛中和HIV-1抗体，提高宿主清除能力。最后，基因编辑将用于 体内靶向和消除潜伏的前病毒不服从LRAS。RF1、RF2的研究成果 而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治愈的治疗方法，并将在顶峰目标中进行测试，以建立概念验证 用于NHP模型中的这些策略，并使其能够转化为临床。

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.