Therapeutic control of HSK by CD80

项目摘要 眼部原发单纯疱疹病毒1型(HSV-1)感染后，病毒在眼睛内复制 并在三叉神经节(TG)建立潜伏期。在潜伏感染的个体中，病毒可以 偶尔会重新激活并返回到眼睛，导致疾病复发。从延迟中重新激活是 单纯疱疹病毒1型眼部感染中角膜瘢痕形成的主要原因。我们以前已经展示过， 单独的中和抗体可以保护免疫的小鼠免于眼睛疾病和死亡；然而，它不能。 保护免疫小鼠免受病毒在眼内复制和TG潜伏期的建立。我们 因此集中在HSV-1可能颠覆免疫系统清除 病毒，限制病毒载量，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 和甘油三酯，这反过来导致较低的有效和延迟清除病毒和 增加了建立潜伏期的敏感性，但同时保护主机免受HSV-1诱导的影响 病理学。我们已发表的和初步的研究确定了免疫反应调节机制 可能是有针对性的，以增强疫苗减少HSV-1在眼睛中复制并防止潜伏的能力- 重新激活。通过完成这些研究，我们希望找到一种新的方法来生产疫苗 预防性和治疗性应用，可以控制急性和潜伏感染，而不会产生不良影响 效果。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。总体而言，我们的具体目标侧重于理解 免疫逃逸机制，保护宿主免受增加的病理影响，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 眼部感染的HSV-1感染、潜伏期重新激活和眼部疾病；以及(2)确定 表达CD80的重组HSV-1(HSV-CD80)或缺失ICP22的病毒对CS的加重作用 抑制作用与PD-L1的存在有关，而与CD28或CTLA4无关。 临床意义：HSV-1感染是中国最常见的严重病毒性眼部感染之一 是病毒致盲的主要原因。这项研究产生的结果可能会 建立一种以前未描述的潜在病毒免疫逃避机制，可被利用来 更好地管理HSV感染。鉴于最近一次大规模的HSV-1第三阶段疫苗试验失败，我们的 这种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.