Therapeutic control of HSK by CD80

CD80 对 HSK 的治疗控制

基本信息

  • 批准号:
    10357919
  • 负责人:
  • 金额:
    $ 40.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

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.
项目摘要 眼部原发性单纯疱疹病毒1型(HSV-1)感染后,病毒在眼部复制 并在三叉神经节(TG)中建立潜伏期。在潜伏感染的个体中,病毒可以 偶尔会重新激活并返回眼睛,导致复发性疾病。这种从延迟中的重新激活是 HSV-1眼感染中角膜瘢痕形成(CS)的主要原因。我们以前已经证明, 中和抗体单独可以保护免疫小鼠免于眼部疾病和死亡;然而, 保护免疫的小鼠免于在眼睛中病毒复制和在TG中潜伏期的建立。我们 因此,研究重点是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ICP 22 抑制宿主CD 80共刺激分子,这导致眼内CD 8 + CTL活性降低 和TG,这反过来又导致病毒清除效率降低和延迟, 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 病理我们已发表的和初步的研究确定了免疫应答调节机制, 可以靶向增强疫苗减少HSV-1在眼睛中复制和预防潜伏期的能力- 重新激活通过完成这些研究,我们希望确定一种新的方法来产生疫苗, 预防性和治疗性应用,可以控制急性和潜伏感染,而不会产生不良反应 方面的影响.这将通过了解ICP 22和CD 80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ICP 22与CD 80启动子的结合是否会增加原发性 HSV-1感染、潜伏期再激活和眼部感染小鼠的眼部疾病;和(2)确定是否 表达CD 80的重组HSV-1(HSV-CD 80)或缺乏ICP的病毒导致CS恶化22 抑制作用与PD-L1的存在有关,而与CD 28或CTLA 4无关。 临床意义:HSV-1感染是世界上最常见的严重病毒性眼部感染之一。 美国是病毒性失明的主要原因。这项研究产生的结果将有可能 建立了一种以前未描述的病毒免疫逃避机制, 更好地控制HSV感染。鉴于最近大规模III期HSV-1疫苗试验的失败, 这种方法可能有助于设计更有效的疫苗。

项目成果

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HOMAYON GHIASI其他文献

HOMAYON GHIASI的其他文献

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{{ truncateString('HOMAYON GHIASI', 18)}}的其他基金

Role of type 1 IFN in eye infection
1 型干扰素在眼部感染中的作用
  • 批准号:
    10732600
  • 财政年份:
    2023
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis
2 型先天淋巴细胞 (ILC2) 在视神经炎中的作用
  • 批准号:
    10359644
  • 财政年份:
    2021
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of type 2 Innate Lymphoid Cells (ILC2s) in optic neuritis
2 型先天淋巴细胞 (ILC2) 在视神经炎中的作用
  • 批准号:
    10357860
  • 财政年份:
    2019
  • 资助金额:
    $ 40.5万
  • 项目类别:
Ocular HSV: Mechanism of virus reactivation
眼部 HSV:病毒再激活机制
  • 批准号:
    10165727
  • 财政年份:
    2018
  • 资助金额:
    $ 40.5万
  • 项目类别:
Ocular HSV: Mechanism of virus reactivation
眼部 HSV:病毒再激活机制
  • 批准号:
    10649980
  • 财政年份:
    2018
  • 资助金额:
    $ 40.5万
  • 项目类别:
Therapeutic control of HSK by CD80
CD80 对 HSK 的治疗控制
  • 批准号:
    10534160
  • 财政年份:
    2016
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
  • 批准号:
    9144799
  • 财政年份:
    2015
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
  • 批准号:
    9759926
  • 财政年份:
    2015
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
  • 批准号:
    9330866
  • 财政年份:
    2015
  • 资助金额:
    $ 40.5万
  • 项目类别:
Role of macrophages in control of ocular HSV
巨噬细胞在控制眼部 HSV 中的作用
  • 批准号:
    10222691
  • 财政年份:
    2015
  • 资助金额:
    $ 40.5万
  • 项目类别:

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