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）感染的发病机制涉及 重要的病毒-神经元相互作用 在原发性粘膜皮肤 感染，病毒通过逆行轴突从入口传播 运输过程中的感觉神经节神经元，它可以逃避 免疫系统通过建立非复制潜伏感染。 的 潜伏感染的神经元是病毒的储存库， 复发性HSV疾病。 神经元可以周期性地激活潜伏的 病毒复制能力的状态。 重新激活的病毒通过 顺行运输过程到皮肤部位， 复制导致复发性感染。 而抗病毒药物，如 阿昔洛韦在限制病毒复制方面是有效的， 病毒的运输和潜伏期 无环鸟苷未能影响 潜伏期和抗药性病毒株的出现说明了 需要新的治疗方式。 我们的假设是药物可以 被设计用来破坏重要的病毒-神经元 交互. 使用一种特征良好的生殖器HSV豚鼠模型 我们已经证明，辣椒素，一种选择性 中断感觉神经元功能，有效地控制初级和 复发性生殖器疾病 由于辣椒素不能抑制病毒 复制我们假设它的影响是由于破坏 重要的病毒-神经元相互作用 在本申请中，我们提出 进一步探讨机制（S）通过香草素影响 皮肤粘膜HSV感染的发病机制。 使用辣椒素类似物 以及已知的受体激动剂和拮抗剂，我们将探讨 辣椒素受体及相关阳离子通道 对HSV疾病的影响 使用胎鼠背根神经节神经元 在双室培养系统中生长，我们将表征辣椒素的 对神经元内病毒运输的影响。 利用最近开发的 分子生物学方法和良好表征的豚鼠模型 生殖器疱疹的症状有哪些？ 潜伏感染建立和维持。 使用体内模型 紫外线辐射诱导的复活，我们将调查 辣椒素对潜伏病毒再活化的影响 总的来说， 这些研究将产生关于病毒-神经元 这种互动有助于小说的理性发展 类抗HSV药物。