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)感染的发病机制包括 基本的病毒-神经细胞相互作用。在初级粘膜皮肤期间 感染，病毒通过逆行轴突从入口传播 将过程运送到感觉神经节神经元，在那里它可以逃避 免疫系统通过建立一种非复制的潜伏感染。这个 潜伏感染神经元是病毒的储存库，负责 复发性单纯疱疹病毒病。神经元可以周期性地重新激活潜伏期 病毒进入复制能力状态。然后，重新激活的病毒通过 顺行运输过程到皮肤部位，在那里进一步 复制会导致反复感染。而抗病毒药物，如 阿昔洛韦在限制病毒复制方面是有效的，它们没有作用 病毒传播或潜伏期。阿昔洛韦未能对患者产生影响 潜伏期和抗药性病毒株的出现说明了 需要新的治疗方式。我们的假设是毒品可以 被开发出来，旨在破坏基本的病毒神经元 互动。使用具有良好特征的生殖器单纯疱疹病毒豚鼠模型 我们已经证明了辣椒素，一种选择性地 干扰感觉神经元功能，有效地控制初级和 复发性生殖器疾病。因为辣椒素不能抑制病毒 我们假设，复制的影响是由于 基本的病毒-神经元相互作用。在本申请中，我们建议 进一步探讨香草素影响植物生长发育的机制(S) 皮肤粘膜单纯疱疹病毒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，我们将探索其作用 辣椒素中的香草素受体及其相关阳离子通道 对单纯疱疹病毒病的影响。用胎鼠背根神经节神经元 在两室培养系统中生长，我们将描述辣椒素 对神经细胞内病毒传播的影响。使用最近开发的 分子生物学方法与特征化的豚鼠模型 对于生殖器疱疹，我们将研究辣椒素对 潜伏感染的建立和维持。使用体内模型 我们将研究紫外线辐射诱导的再激活 辣椒素对潜伏病毒复活的影响。总而言之， 这些研究将产生有关病毒神经元的重要新信息。 促进小说理性发展的互动 类抗单纯疱疹病毒药物。