Targeting PD-1 Pathway for Functional Cure of AIDS

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疗法的情况下）使用SIV/猕猴模型用于HIV/AIDS。功能障碍性抗- 艾滋病毒免疫和病毒宿主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。我们认为，这两个问题是可以解决的， 我们最近的研究表明， PD-1阻断与ART协同作用，以增强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值得注意的，因为这是在动物中观察到的， 在SIV感染后30周进行ART，此时对宿主免疫系统的损害 严重的话，病毒会积累很多逃逸突变。多项研究，包括我们的 我们已经证明，在ART期间，病毒库集中在GC-Tfh中， 产生具有归巢至GC潜力的抗病毒CD 8 T细胞。然而，直到最近， 抗病毒的CD 8 T细胞不以GC为家。然而，其他人和我们最近定义了一个新的子集， CXCR 5 + CD 8 T细胞具有归巢GC（滤泡CD 8）的潜力，有助于控制SIV。 重要的是，我们现在知道CD 40 L佐剂DNA/MVA疫苗可以诱导CXCR 5 + CD 8 T细胞， 在SIV未感染的恒河猴中。正在进行的研究正在探讨PD- 1的阻断，使用CD 40 L和TLR 7/8激动剂作为佐剂的治疗性疫苗接种。基于这些 结果我们提出了以下3个重点领域，为未来5年的这一R37：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CD 8 T细胞的产生。领域3 -目标确定 PD-1阻断SIV感染的细胞。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HIV/AIDS功能性治愈。 相关性（参见说明）： 世卫组织估计，目前有3200万人感染艾滋病毒/艾滋病。非常需要 开发治疗方法，实现功能性治愈（长期控制艾滋病毒在没有 联合抗逆转录病毒疗法）。这项赠款的目标是确定一种功能性治疗艾滋病毒的目标， 使用抗PD-1抗体联合ART和疫苗接种的PD-1抑制途径。

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.