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：
10091378
负责人：
Rama Rao Amara
金额：
$ 84.92万
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/10091378
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 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 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 programmed cell death protein 1 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封锁的安全性和治疗潜力 PD-1（编程死亡-1）共同抑制途径以实现功能治疗（长期控制）在没有抗逆转录病毒疗法的情况下）使用SIV/猕猴模型用于HIV/AID。功能失调的抗艾滋病毒的免疫力和病毒储层的持久性代表了必须解决的两个主要问题通过理论方法，针对功能治疗的方法。我们相信这两个问题可以解决通过靶向PD-1共抑制途径有效地。我们最近的研究表明 PD-1桶与ART协同作用，以增强ART中断后对病毒反弹的控制最多6-80倍。我们认为这些结果非常出色，因为这是在动物中观察到的在SIV感染后30周内受到ART的损害很严重，病毒会积累许多逃生突变。包括我们的多项研究自己已经证明，在艺术期间，病毒储层集中在GC-TFH中，至关重要产生具有GC的抗病毒CD8 T细胞。但是，直到最近的教条该抗病毒CD8 T细胞不属于GC。但是，其他人和我们最近定义了一个新颖的子集 CXCR5+ CD8 T细胞的可能性可能是GC（卵泡CD8），并有助于控制SIV。重要的是，我们现在知道CD40L辅助DNA/MVA疫苗可以诱导CXCR5+ CD8 T细胞在SIV中未感染的恒河猕猴。正在进行的研究正在解决合并PD-的效率 1使用CD40L和TLR7/8激动剂作为调节器，与治疗疫苗接种的1桶。基于这些结果我们在此R37的接下来的5年中提出以下3个重点区域：区域1 - 协同作用在PD-1桶，热疫苗接种和其他免疫疗法之间。区域 2 - 优化条件以改善卵泡归巢CD8 T细胞的产生。区域3 - 目标 PD-1阻断对SIV感染的细胞。通过完成这些研究，我们希望发展有效免疫疗法以实现艾滋病毒/艾滋病的功能治疗。相关性（请参阅说明）：谁估计目前有3200万人患有艾滋病毒/艾滋病。非常需要开发治疗的治疗方法（实现了功能性治疗）（在没有艾滋病毒的长期控制组合抗逆转录病毒疗法）。这笔赠款的目的是通过靶向识别艾滋病毒的功能治疗 PD-1抑制途径使用抗PD-1抗体与ART和疫苗接种结合。