Targeting PD-1 Pathway for Functional Cure of AIDS

靶向 PD-1 通路实现艾滋病功能性治愈

基本信息

批准号：
9545114
负责人：
Rama Rao Amara
金额：
$ 91.11万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9545114
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Adjuvant Agonist Animals Antibodies Antiviral Agents Area Award BLR1 gene Binding CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Coculture Techniques Contracts DNA/MVA vaccine Data Dose Funding Generations Goals Grant HIV Home environment Homing Human Immune system Immunity Immunologics Immunotherapy In Vitro Infection Instruction Interruption Macaca Macaca mulatta Manuscripts Modeling Mutation PD-1 blockade PD-1 pathway Pathway interactions Principal Investigator Progress Reports Research SIV SLEB2 gene Safety System T-Lymphocyte TLR7 gene TNFSF5 gene Therapeutic Time Vaccination Vaccine Therapy Viral Viral Physiology Viral reservoir Virus Work anti-PD-1 anti-PD1 antibodies antiretroviral therapy base density efficacy testing experimental study improved in vivo novel programs synergism viral rebound

项目摘要

The overall goal of this proposal is to evaluate the safety and therapeutic potential of in vivo blockade of the PD-1 (Programmed death-1) co-inhibitory pathway to achieve a functional cure (long-term control in the absence of antiretroviral therapy) for HIV/AIDS using the SIV/macaque model. Dysfunctional anti- HIV immunity and persistence of viral reservoirs represent the two major issues that must be addressed by therapeutic approaches targeting functional cure. We believe that these two issues can be addressed effectively by targeting the PD-1 co-inhibitory pathway d uring ART. Our recent studies have demonstrated that PD-1 blockade synergizes with ART to enhance control of viral rebound following ART interruption up to 6-80 fold. We think these results are remarkable since this was observed in animals that were subjected to ART at 30 weeks after SIV infection by which time the damage to the host immune system was severe and virus would have accumulated many escape mutations. Multiple studies including our own have demonstrated that viral reservoirs are concentrated in GC-Tfh during ART and it is critical to generate anti-viral CD8 T cells with homing potential to GC. However, the dogma until recently has been that anti-viral CD8 T cells do not home to GC. However, others and we recently defined a novel subset of CXCR5+ CD8 T cells with potential to home to GC (Follicular CD8) and contribute to control of SIV. Importantly, we now know that CD40L-adjuvanted DNA/MVA vaccine can induce CXCR5+ CD8 T cells in SIV uninfected rhesus macaques. The ongoing studies are addressing the efficacy of combining PD- 1 blockade with therapeutic vaccination using CD40L and TLR7/8 agonist as adjuvants. Based on these results we propose the following 3 focus areas for the next 5 years of this R37: Area 1 – Synergy between PD-1 blockade, therapeutic vaccination and other immunotherapies. Area 2 – Optimizing conditions to improve generation of follicular homing CD8 T cells. Area 3 – Targeting the PD-1 blockade to SIV-infected cells. By completion of these studies, we hope to develop an effective immunotherapy to achieve functional cure for HIV/AIDS. RELEVANCE (See instructions): WHO estimates that there are currently 32 Million humans living with HIV/AIDS. There is a great need for developing therapeutic approached that achieve functional cure (long term control of HIV in the absence of combination antiretroviral therapy). The goal of this grant is to identify a functional cure for HIV by targeting PD-1 inhibitory pathway using anti-PD-1 antibody combined with ART and vaccination.

该提案的总体目标是评估体内阻断的安全性和治疗潜力 PD-1（程序性死亡-1）共抑制途径以实现功能性治愈（长期控制在没有抗逆转录病毒治疗的情况下）使用SIV/猕猴模型治疗艾滋病毒/艾滋病。 HIV免疫和病毒储存库的持续存在是必须解决的两个主要问题我们相信通过针对功能性治愈的治疗方法可以解决这两个问题。我们最近的研究表明，通过在 ART 期间有效靶向 PD-1 共抑制途径。 PD-1 阻断与 ART 具有协同作用，可增强对 ART 中断后病毒反弹的控制我们认为这些结果是显着的，因为这是在动物身上观察到的。感染 SIV 后 30 周接受 ART，此时宿主免疫系统受到损害情况很严重，病毒会积累许多逃逸突变，包括我们的多项研究。自己已经证明，在 ART 期间，病毒储存库集中在 GC-Tfh 中，因此至关重要产生具有 GC 归巢潜力的抗病毒 CD8 T 细胞然而，直到最近，这一教条仍然存在。然而，其他人和我们最近定义了一个新的亚群。 CXCR5+ CD8 T 细胞有可能归巢于 GC（滤泡 CD8）并有助于控制 SIV。重要的是，我们现在知道 CD40L 佐剂 DNA/MVA 疫苗可以诱导 CXCR5+ CD8 T 细胞正在进行的研究正在探讨联合使用 PD- 的功效。 1 使用CD40L和TLR7/8激动剂作为佐剂的疫苗阻断治疗。根据结果，我们建议 R37 未来 5 年的以下 3 个重点领域：领域 1 – 协同作用 PD-1 阻断、治疗性疫苗接种和其他免疫疗法之间的关系。 2 – 优化条件以改善滤泡归巢 CD8 T 细胞的生成区域 3 – 靶向。通过完成这些研究，我们希望开发出一种有效的 PD-1 阻断 SIV 感染细胞的方法。免疫疗法实现艾滋病毒/艾滋病的功能性治愈。相关性（参见说明）：世界卫生组织估计，目前有 3200 万人感染艾滋病毒/艾滋病，因此迫切需要艾滋病毒/艾滋病。开发实现功能性治愈的治疗方法（在缺乏治疗的情况下长期控制艾滋病毒）联合抗逆转录病毒疗法）这项资助的目标是通过靶向确定艾滋病毒的功能性治愈方法。使用抗 PD-1 联合抗体结合 ART 和疫苗接种的 PD-1 抑制途径。