EXPERIMENTAL PATHOGENESIS & THERAPY OF OCULAR ADENOVIRUS

腺病毒是外眼最常见的感染原因 执业眼科医生在全球范围内遇到的疾病，但 它们实际上仍然无法治愈。目前还没有抗病毒药物 可用于根除眼睛中的病毒或防止其传播的试剂。 此外，一些内科医生目前在美国使用类固醇 腺病毒眼病的治疗存在很大争议，主要是 因为它们的有效性缺乏明确性。我们有 发展并建立了腺病毒致病的动物模型 使用新西兰兔的眼睛，并成功地使用了这个 开发和测试有效对抗病毒的潜在抗病毒药物的模式 腺病毒及其引起的眼部疾病。在即将到来的续订中， 我们计划用它来解决治疗、预防和治疗的进一步方面 腺病毒眼病的发病机制。有两个 明确的目标。首先，我们计划评估一个非常有前途的广泛 光谱抗病毒药物HPMPC，一种体外有效的抗病毒药物 腺病毒和疱疹病毒都有。目标的一部分将是 建立高浓度、罕见剂量的有效治疗方案 腺病毒眼病的治疗和预防。第二部分 将致力于了解这种药物的作用机制和 对它的抗药性的发展。这将涉及到隔离和 抗HPMPC SO的腺病毒及HSV-1突变体的特性研究 我们可以确定HPMPC的病毒靶点，通过什么机制 对该制剂产生抗药性，这种抗药性对 这些病毒在眼睛里的致病机制。第二个目标是 腺病毒眼部致病机制的两个方面。在这个目标的第一部分， 我们将使用动物模型来解决局部类固醇在 治疗，不仅对腺病毒眼的延迟性发作 这种疾病不仅发生在病毒的急性复制阶段，还发生在感染的急性阶段。 这一目标的第二部分将研究寄主的机制 腺病毒5型扩大到新西兰兔的范围，基础 为了我们的眼睛模型。从这些研究中，我们希望确定 在治疗、管理和理解中非常重要的参数 由腺病毒引起的人类眼病的发病机制。

Adenoviruses are the most common infectious causes of external ocular disease encountered worldwide by the practicing ophthalmologist, and yet they remain virtually untreatable. There are currently no antiviral agents available to eradicate virus from the eye or prevent its spread. Furthermore, the current use of steroids by some physicians in the treatment of adenovirus eye disease is highly controversial, mostly because of lack of clarity concerning their effectiveness. We have developed and established an animal model of adenovirus pathogenesis in the eye using the New Zealand rabbit, and have successfully used this model to develop and test potential antiviral agents effective against adenoviruses and the eye diseases they cause. In the upcoming renewal, we plan to use it to address further aspects of treatment, prevention and the mechanisms of pathogenesis of adenovirus eye disease. There are two specific aims. In the first, we plan to evaluate a very promising broad spectrum antiviral drug, HPMPC, a drug that is effective in vitro against both adenoviruses and herpesviruses. Part of the aim will be to establish high concentration, infrequent dosage regimens effective at treatment and prevention of adenovirus ocular disease. The second part will aim to understand the mechanisms by which this drug acts and the development of resistance to it. This will involve the isolation and characterization of adenovirus and HSV-1 mutants resistant to HPMPC so that we may identify the viral target of HPMPC, the mechanisms by which resistance to the agent develops, and the effect of such resistance upon the pathogenesis of these viruses in the eye. The second aim concerns two aspects of adenovirus ocular pathogenesis. In part one of this aim, we will use the animal model to address the use of topical steroids in the treatment, not only of the delayed onset aspect of adenoviral eye disease, but also of the acute viral replicative phase of the infection. The second part of this aim will be to investigate the mechanisms of host range extension of adenovirus type 5 to the New Zealand rabbit, the basis for our ocular model. From these studies, we hope to establish parameters important in the treatment, management and understanding of pathogenesis of eye disease caused by adenoviruses in humans.