Ocular HSV-1: Turning On/Off LAT Expression in Latency

眼部 HSV-1：在潜伏期打开/关闭 LAT 表达

• 批准号: 6601178
• 负责人: GUEY-CHUEN PERNG
• 金额: $ 4.52万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6601178
• 关键词: gene expression; gene induction /repression; gene mutation; genetically modified animals; herpes simplex virus 1; laboratory rabbit; latent virus infection; molecular cloning; northern blottings; ocular herpes; regulatory gene; relapse /recurrence; southern blotting; virus infection mechanism

DESCRIPTION: (Applicant's Abstract) Recurrent herpes simplex virus type I (HSV-1) infection is a major cause of viral induced blindness. Although the HSV-1 LAT gene is essential for efficient spontaneous reactivation, it remains unclear whether LAT's main latency related function takes place during establishment of latency or reactivation from latency. Although LAT can enhance the rate at which latency is established by 2-3 fold, it can enhances spontaneous reactivation by up to 10-fold. In addition, a mutation in a gene other than LAT has been shown to reduce establishment of latency by 20-fold without altering spontaneous reactivation. We hypothesize that LAT has an important function during the reactivation stage of the HSV-1 latency reactivation cycle. This would make LAT an excellent target for therapeutic intervention to block recurrent disease, and would have tremendous clinical significance. Our specific aim is to construct and then infect rabbits with an HSV-1 mutant in which LAT is expressed only when Dox is present.in the rabbit's water supply. Dox will be fed either (i)just prior to and then throughout the first 21 days of infection (LAT will be active only during the time of establishment of latency) or (ii)continuously from days 22 to 60 post infection (pi) (LAT will be active only during the time of reactivation from latency). Spontaneous reactivation will be determined from 30 to 60 days pi. We expect these two complementary experiments to show that LAT is important during reactivation. Thus, (i)when LAT is active only during establishment we expect spontaneous reactivation to be reduced to LAT null mutants levels; and (10when LAT is active only during reactivation we expect wild type spontaneous reactivation levels. These results would confirm that LAT is important at the reactivation step and suggest that blocking LAT's function would be an outstanding therapeutic approach for eliminating or reducing recurrent HSV-1 ocular disease in individuals with a history of recurrent ocular HSV-1.

描述：（申请人的摘要）复发性单纯疱疹病毒I型 HSV-1感染是病毒性失明的主要原因。虽然 HSV-1 LAT基因对于有效的自发再活化是必需的，它仍然是 不清楚LAT的主要延迟相关功能是否发生在 建立潜伏期或从潜伏期重新激活。尽管LAT可以增强 潜伏期建立的速率增加2-3倍， 自发再活化高达10倍。另外，基因突变 除LAT外，其他方法已显示可将建立延迟缩短20倍 而不改变自发的再激活。 我们假设LAT在再激活阶段具有重要功能 HSV-1潜伏期再激活周期这将使一个优秀的 治疗干预的目标，以阻止复发性疾病，并将有 巨大的临床意义。 我们的具体目标是构建HSV-1突变体，然后用其感染家兔 其中LAT仅在Dox是兔子的水时present.in 供应Dox将在（i）第一次给药前和第一次给药期间给药 感染21天（LAT仅在建立期间有效 或（ii）从感染后第22至60天（pi）连续（LAT 将仅在从等待时间重新激活期间有效）。自发 将在感染后30至60天确定再激活。我们希望这两个人 补充实验表明LAT在再激活过程中很重要。 因此，（i）当LAT仅在建立期间活跃时，我们预期是自发的 再激活降低到LAT无效突变体水平;和（10当LAT为 我们预期野生型仅在再激活期间才有活性， 程度.这些结果将证实LAT在再激活时很重要 步骤，并建议阻止土地增值税的功能将是一个突出的 消除或减少复发性HSV-1眼病的治疗方法 在具有复发性眼部HSV-1病史的个体中。