VANILLOIDS AND HSV--MOLECULAR AND STRUCTURAL ANALYSIS

香草酸和 HSV——分子和结构分析

• 批准号: 2442647
• 负责人: Lawrence Raymond Stanberry
• 金额: $ 21.31万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442647
• 关键词: Herpes simplex disease; antiviral agents; capsaicin; disease /disorder model; dorsal root; embryo /fetus; genital herpes; guinea pigs; herpes simplex virus 2; host organism interaction; laboratory rabbit; laboratory rat; molecular pathology; neurons; pathologic process; spinal ganglion; ultraviolet radiation

The pathogenesis of herpes simplex virus (HSV) infections involves essential virus-neuuron interactions. During primary mucocutaneous infection, virus spreads from the portal of entry via retrograde axonal transport processes to sensory ganglion neurons where it can evade the immune system by establishing a non-replicating latent infection. The latently infected neuron is the reservoir of virus responsible for recurrent HSV disease. Periodically, the neuron can reactivate latent virus to a replication competent state. Reactivated virus then moves via anterograde transport processes to cutaneous sites where further replication results in recurrent infection. While antiviral drugs like acyclovir are effective at limiting viral replication, they have no effect on viral transport or latency. The failure of acyclovir to impact on latency and the emergence o drug resistant virus strains illustrate the need for new treatment modalities. It is our supposition that drugs can be developed that are designed to disrupt essential virus-neuron interactions. Using a well characterized guinea pig model of genital HSV infection we have shown that capsaicin, a vanilloid that selectively interrupts sensory neuron functions, effectively controls both primary and recurrent genital disease. Since capsaicin does not inhibit viral replication we postulate that its effects result from the disruption of essential virus-neuron interactions. In this application we propose to further explore the mechanism(s) by which vanilloids affect the pathogenesis of mucocutaneous HSV infections. Using capsaicin analogues and known receptor agonists and antagonists we will explore the role of the vanilloid receptor and associated cation channel in capsaicin's effects on HSV disease. Using fetal rat dorsal root ganglion neurons grown in a two-chamber culture system we will characterize capsaicin's effects on intraneuronal virus transport. Using recently developed molecular biological methods and the well characterized guinea pig model of genital herpes, we will examine the effects of capsaicin on the establishment and maintenance of latent infection. Using an in vivo model of ultraviolet radiation-induced reactivation we will investigate the effect of capsaicin on the reactivation of latent virus. Collectively, these studies will yield important new information about virus-neuron interactions which will facilitate the rational development of a novel class of anti-HSV drugs.

单纯疱疹病毒（HSV）感染的发病机理涉及 必需的病毒神经元相互作用。 在原发性粘膜皮肤病期间 感染，病毒通过逆行轴突从入口传播 将过程转移到感觉神经节神经元可以逃避 通过建立非复制潜在感染来免疫系统。 这 潜在感染的神经元是导致病毒的水库 复发性HSV疾病。 周期性地，神经元可以重新激活潜在 病毒具有复制能力状态。 重新激活的病毒然后通过 顺行传输过程到皮肤地点进一步 复制导致复发感染。 而抗病毒药也喜欢 Acyclovir有效地限制病毒复制，它们没有影响 关于病毒运输或潜伏期。 Acyclovir未能影响 潜伏期和出现o抗药性病毒菌株说明了 需要新的治疗方式。 我们认为毒品可以 被开发旨在破坏必需病毒神经元 互动。 使用良好的生殖器HSV的豚鼠模型 感染我们已经表明，辣椒素是一种有选择性的香草素 中断感觉神经元功能，有效地控制原发性和 复发性生殖器疾病。 由于辣椒素不抑制病毒 复制我们假设其影响是由于中断而导致的 必需病毒 - 神经元相互作用。 在此应用程序中，我们建议 进一步探讨了香草素影响的机制 粘膜皮肤HSV感染的发病机理。 使用辣椒素类似物 以及已知的受体激动剂和对手，我们将探讨 辣椒素的香草素受体和相关的阳离子通道 对HSV疾病的影响。 使用胎儿大鼠背根神经神经元 在两室文化系统中生长，我们将描述辣椒素的 对神经内病毒转运的影响。 使用最近开发的 分子生物学方法和良好的豚鼠模型 在生殖器疱疹中，我们将研究辣椒素对 潜在感染的建立和维护。 使用体内模型 紫外线辐射引起的重新激活，我们将研究 辣椒素对潜在病毒重新激活的影响。 共同 这些研究将产生有关病毒神经元的重要新信息 互动将促进小说的理性发展 抗HSV药物类别。