Targeting PD-1 Pathway for Functional Cure of AIDS

这项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)共抑制通路实现功能性治愈(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- 艾滋病毒免疫和病毒库的持久性是必须解决的两个主要问题 通过以功能治愈为目标的治疗方法。我们认为，这两个问题是可以解决的 在抗逆转录病毒治疗过程中通过靶向PD-1共抑制通路有效。我们最近的研究表明 PD-1阻滞剂与ART协同作用以增强ART阻断后病毒反弹的控制 最高可达6-80折。我们认为这些结果是值得注意的，因为这是在 在感染SIV后30周接受ART，此时宿主免疫系统受到损害 是严重的，病毒会积累许多逃逸突变。多项研究，包括我们的 OWN已经证明，在抗逆转录病毒治疗期间，病毒库集中在GC-TFH中，这对 产生具有归巢潜能的抗病毒CD8 T细胞。然而，直到最近，人们的教条一直是 抗病毒的CD8T细胞不是GC的归宿。然而，其他人和我们最近定义了一个新的子集 CXCR5+CD8 T细胞有可能与GC(卵泡CD8)结合，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SIV未感染的恒河猴中。正在进行的研究正在讨论联合帕金森病和帕金森病的疗效。 1以CD40L和TLR7/8激动剂为佐剂的治疗性疫苗阻断。基于这些 结果我们提出了R37未来5年的以下3个重点领域：领域1-协同 在PD-1阻断、治疗性疫苗接种和其他免疫疗法之间。面积 2-优化条件以提高滤泡归巢CD8 T细胞的生成。区域3--目标定位 PD-1对SIV感染细胞的阻断作用。通过完成这些研究，我们希望制定一个有效的 免疫疗法，以实现艾滋病毒/艾滋病的功能性治愈。 相关性(请参阅说明)： 世卫组织估计，目前有3200万人感染艾滋病毒/艾滋病。有很大的需求 开发实现功能性治愈的治疗方法(在缺乏艾滋病毒的情况下长期控制艾滋病毒 联合抗逆转录病毒疗法)。这笔赠款的目标是通过针对性地确定艾滋病毒的有效治疗方法 PD-1抑制途径采用抗PD-1抗体联合ART和疫苗接种。

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.