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

• 批准号: 10349439
• 负责人: Rama Rao Amara
• 金额: $ 82.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10349439
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Agonist; Animals; Antibodies; 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

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。功能失调的抗 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 通过针对功能性治愈的治疗方法。我们相信这两个问题是可以解决的 通过在 ART 期间针对 PD-1 共抑制途径有效地发挥作用。我们最近的研究表明 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 高达6-80倍。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 情况严重时，病毒会积累许多逃逸突变。多项研究，包括我们的 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，这一教条仍然是 抗病毒 CD8 T 细胞并不归巢于 GC。然而，其他人和我们最近定义了一个新的子集 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 在未感染 SIV 的恒河猴中。正在进行的研究正在探讨结合 PD- 1 使用 CD40L 和 TLR7/8 激动剂作为佐剂进行治疗性疫苗接种阻断。基于这些 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。区域 2 – 优化条件以改善滤泡归巢 CD8 T 细胞的生成。区域 3 – 目标定位 PD-1 对 SIV 感染细胞的阻断。通过完成这些研究，我们希望开发出一种有效的 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。非常需要 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） 联合抗逆转录病毒治疗）。这笔赠款的目标是通过靶向治疗来确定艾滋病毒的功能性治愈方法 使用抗PD-1抗体结合ART和疫苗接种的PD-1抑制途径。