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，并与显著的患者发病率有关。 目前，还没有有效的抗病毒疗法，也没有 研究眼部疾病发病机制的动物模型 测试新的抗病毒药物。目前建议的具体目标是：1) 开展眼部腺病毒感染发病机制的研究 新西兰兔眼模型。具体地说，为了确定分子基础 血清型毒力差异及寄主范围的作用机制 在我们的成功模式中扩展广告5；2)评估新的 抗病毒药物在新西兰兔体内和体外的潜在治疗作用 眼睛模型。对44只新西兰兔的初步眼科研究表明 基于病毒血清型的腺病毒致病性差异：AD5 (生殖性感染)、Ad8(流产感染)和Ad19(否 感染)。腺病毒感染的一个成功的眼部模型是 在感染临床分离株Ad5 McEwen的32只新西兰兔身上研制出 采用了双眼设计。可重复性急性眼部感染 连续8天进行病毒复制。高峰眼球 病毒滴度在接种后第3天达到103pfu/ml。并代表了一个二 对数增加(X100)超过胫炎(24/32眼，75%)，并延迟 假定免疫介导的临床疾病的发病：眼睑结膜炎 (21/32眼，66%)，虹膜炎(29/32眼，91%)，角膜水肿 (32/32眼，100%)和角膜上皮下浸润性病变(30/32 眼睛，94%)。S-HMPHA和HMPHA体外抗病毒作用的初步研究 2‘-Nor-cGMP对几种人 眼部血清型：Ad5、Ad8和Ad19。目前的建议旨在 在我们新的活体兔眼模型中测试这些有希望的药物。这个 申请者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，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.