EXPERIMENTAL PATHOGENESIS & THERAPY OF OCULAR ADENOVIRUS

描述（申请人摘要）：眼部腺病毒感染发生在 在世界范围内流行，并且与显著的患者发病率相关。 目前，还没有有效的抗病毒治疗，也没有一种抗病毒药物。 动物模型，在其中研究眼病的发病机理或 测试新的抗病毒药物 目前建议的具体目标是：1） 开始研究腺病毒眼部感染的发病机制， 新西兰兔眼模型。 具体来说，为了确定 血清型毒力差异和宿主范围的机制 在我们成功的模型中，Ad 5的延伸;以及2）评估新的 抗病毒药物作为体外和新西兰兔的潜在治疗药物 眼模型 对44只新西兰兔的初步眼部研究表明， 基于病毒血清型的腺病毒致病性差异：Ad 5 （生产性感染）、Ad 8（流产性感染）和Ad 19（无 感染）。 一个成功的腺病毒感染眼模型是 在感染Ad 5麦克尤恩（一种临床分离株）的32只新西兰兔中， 使用了一种双眼设计。 可再现的急性眼部感染是 连续8天的病毒复制。 峰值目镜 在感染后第3天达到病毒滴度（103 pfu/ml）。代表了一个2 对数增加（x100）超过结膜炎（24/32只眼，75%），并延迟 发生假定免疫介导的临床疾病：睑结膜炎 (21虹膜炎（29/32眼，91%），角膜水肿 (32角膜上皮下浸润（30/32眼，100%） 眼睛，94%）。 使用S-HMPHA和 2 '-nor-cGMP显示出对几种人类的有效抑制活性。 眼部血清型：Ad 5、Ad 8和Ad 19。 目前的建议旨在 在我们的新的体内兔眼模型中测试这些有前途的药物。 的 申请人的长期目标是更好地了解 腺病毒眼部感染发病机制的分子基础， 开发有效的治疗方法，以减少患者的痛苦。

DESCRIPTION (applicant's abstract): Ocular adenoviral infections occur in epidemics worldwide, and are associated with significant patient morbidity. Currently, there is no effective antiviral therapy, nor has there been an animal model in which to study the pathogenesis of ocular disease or to test new antivirals. The specific aims of the current proposal are: 1) to begin the study of the pathogenesis of adenoviral ocular infection in our NZ rabbit ocular model. Specifically, to determine the molecular basis for differences in serotype virulence, and the mechanism of host range extension of Ad 5 in our successful model; and 2) to evaluate new antivirals as potential therapeutic agents in vitro and in the NZ rabbit ocular model. Preliminary ocular studies in 44 NZ rabbits suggested differences in adenovirus pathogenicity based on viral serotype: Ad 5 (productive infection), Ad 8 (abortive infection), and Ad 19 (no infection). A successful ocular model of adenovirus infection was developed in 32 NZ rabbits infected with Ad 5 McEwen, a clinical isolate, using a paired-eye design. Reproducible acute ocular infection was demonstrated with viral replication for 8 consecutive days. Peak ocular viral titers (103 pfu/ml) were achieved on day 3 p.i. and represented a two log increase (x100) over tivitis (24/32 eyes, 75 percent), and delayed onset of presumed immune-mediated clinical disease: blepharoconjunctivitis (21/32 eyes, 66 percent), iritis (29/32 eyes, 91 percent), corneal edema (32/32 eyes, 100 percent), and subepithelial corneal infiltrates (30/32 eyes, 94 percent). Preliminary in vitro antiviral studies with S-HMPHA and 2'-nor-cGMP demonstrated potent inhibitory activity against several human ocular serotypes: Ad 5, Ad 8, and Ad 19. The current proposal seeks to test these promising agents in our new in vivo rabbit ocular model. The applicant's long term goals are to achieve a better understanding of the molecular basis of the pathogenesis of adenoviral ocular infections, and to develop effective treatment to reduce patient suffering.