Therapeutic control of HSK by CD80

项目概要 眼部原发性单纯疱疹病毒 1 型 (HSV-1) 感染后，病毒在眼内复制 并确定三叉神经节 (TG) 的潜伏期。在潜伏感染的个体中，病毒可以 有时会重新激活并返回眼睛，导致疾病复发。这种延迟的重新激活是 HSV-1 眼部感染导致角膜疤痕 (CS) 的主要原因。我们之前已经证明了 单独的中和抗体可以保护免疫小鼠免受眼部疾病和死亡；然而，它并没有 保护免疫小鼠免受眼内病毒复制和 TG 潜伏期的影响。我们 因此，重点关注 HSV-1 可能破坏免疫系统清除病毒的能力的机制。 病毒，限制病毒载量，并防止建立潜伏期。我们已经证明 HSV-1 病毒 ICP22 抑制宿主 CD80 共刺激分子，从而导致眼睛中 CD8 CTL 活性降低 眼部感染小鼠的TG和TG，这反过来又导致病毒清除效果较差和延迟 增加对潜伏期建立的敏感性，但同时保护宿主免受 HSV-1 诱导的侵害 病理学。我们已发表的初步研究确定了免疫反应调节机制 可以有针对性地增强疫苗减少 HSV-1 在眼中复制并防止潜伏期的能力 重新激活。通过完成这些研究，我们希望找到一种新方法来生产疫苗 预防性和治疗性应用可控制急性和潜伏感染而不会产生不良反应 影响。这将通过了解 ICP22 和 CD80 如何协调调节病毒复制来实现 眼睛、眼病和潜伏期再激活。总的来说，我们的具体目标侧重于理解 免疫逃逸机制，保护宿主免受病理增加，同时减少病毒清除。 我们建议：（1）确定阻断 ICP22 与 CD80 启动子的结合是否会增加初级 HSV-1 感染、潜伏期再激活和眼部感染小鼠的眼部疾病； (2) 确定是否 表达 CD80 的重组 HSV-1 (HSV-CD80) 或缺乏 ICP22 的病毒导致 CS 恶化 抑制作用与 PD-L1 的存在相关，但与 CD28 或 CTLA4 无关。 临床意义：HSV-1 感染是最常见的严重病毒性眼部感染之一 在美国，它是病毒性失明的主要原因。这项研究产生的结果可能会 建立一种先前未描述的病毒免疫逃避机制，可用于 更好地控制 HSV 感染。鉴于最近大规模 III 期 HSV-1 疫苗试验失败，我们的 该方法可能有助于设计更有效的疫苗。

Project Summary Following ocular primary herpes simplex virus type-1 (HSV-1) infection, the virus replicates in the eye and establishes latency in the trigeminal ganglia (TG). In a latently infected individual, the virus can occasionally reactivate and travel back to the eye causing recurrent disease. This reactivation from latency is the major cause of corneal scarring (CS) in HSV-1 eye infections. We have shown previously that elicitation of neutralizing antibody alone can protect immunized mice from eye disease and death; however, it does not protect the immunized mice from virus replication in the eye and the establishment of latency in the TG. We therefore focused on the mechanisms by which HSV-1 may subvert the ability of the immune system to clear the virus, limit viral load, and prevent establishment of latency. We have shown that HSV-1 viral ICP22 suppresses the host CD80 co-stimulatory molecule and that this leads to reduced CD8+ CTL activity in the eye and TG of ocularly infected mice, which in turn leads to less effective and delayed clearance of virus and increased susceptibility to establishment of latency but at the same time protect host from HSV-1-induced pathology. Our published and preliminary studies identified immune response regulatory mechanisms that could be targeted to enhance the vaccine’s ability to reduce HSV-1 replication in the eye and prevent latency- reactivation. By completing these studies, we expect to identify a novel approach to generating a vaccine with both prophylactic and therapeutic applications that may control acute and latent infection without adverse effects. This will be achieved by understanding how ICP22 and CD80 coordinately regulate virus replication in the eye, eye disease, and latency-reactivation. Collectively, our Specific Aims focus on understanding mechanisms of immune escape that protect the host from increased pathology while reducing viral clearance. We propose to: (1) Determine whether blocking binding of ICP22 to the CD80 promoter will increase primary HSV-1 infection, latency-reactivation, and eye disease in ocularly infected mice; and (2) Determine whether exacerbation of CS by a recombinant HSV-1 expressing CD80 (HSV-CD80) or by viruses lacking the ICP22 suppressive effect is associated with the presence of PD-L1 but not CD28 or CTLA4. CLINICAL SIGNIFICANCE: HSV-1 infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral-induced blindness. The results generated by this study will potentially establish a previously undescribed mechanism underlying viral immune evasion that could be exploited to better manage HSV infection. In light of recent failure of a large-scale phase III HSV-1 vaccine trials, our approach may help design a more efficacious vaccine.