STUDIES WITH ANIMAL MODELS OF SEXUALLY TRANSMITTED DISEASES

性传播疾病的化学预防是一种 很吸引人的概念。阴道内给药可能会预防 通过使有机体失活而在入口处感染的；堵塞的 依附于穿透力；或干扰专业功能 在疾病发病机制中是必不可少的。促进……发展 控制性病的预防策略我们将采取三项具体措施 目标： 第一，项目1所示的多硫酸盐碳水化合物和表面活性 和2具有最小的细胞毒性，但在体外具有很强的抗肿瘤活性 将对单纯疱疹病毒和/或衣原体进行研究，以确定它们是否可以保护 对抗实验性生殖器感染的豚鼠。阴道内 豚鼠接种单纯疱疹病毒或衣原体可导致感染 与在人类身上观察到的非常相似。这些模型已经被 有助于探索微生物的发病机制，并应预测其疗效 女性局部使用的杀微生物剂。 其次，我们将使用项目1中设计的HSV突变体来探索各方面 生殖器疱疹的发病机制在 局部杀微生物剂的开发。使用缺乏基因的突变体 糖蛋白C(GC)，病毒包膜的一个重要成分，对 病毒粒子的附着，我们将确定GC在 生殖器感染的发病机制。这一信息将确立 GC是否是杀菌作用的潜在靶点。如果 阴道内杀菌剂将有效地预防生殖器 疱疹，它们必须阻止病毒进入感觉神经元。自.以来 关于病毒是如何进入感觉神经的，目前还不清楚。 将使用gB和gD缺陷突变株直接检测HSV 结合并穿透感觉神经末梢或通过细胞进入- 细胞由上皮细胞扩散而来。 第三，我们将探讨预防性治疗的机制。 使用辣椒素的合成异构体，公民酰胺，保护动物免受 生殖器疱疹。阴道内辣椒素不能阻止病毒复制 也不直接灭活HSV，但似乎通过 干扰专门的病毒与神经元的相互作用。即使是简短的 辣椒素治疗可延长其发病机制。 生殖器疱疹。从这些实验中获得的信息可能会使 新的局部活性神经药理药物的开发将 有效预防生殖器单纯疱疹病毒感染。 因此，我们研究的目标是开发局部杀微生物剂 在临床试验中保证进一步的评估，并检查以下方面 生殖器疱疹的发病机制可能有助于合理 用于预防的阴道内化学避孕药的发展 生殖器HSV感染。

The chemoprophylaxis of sexually transmitted diseases (STD) is an attractive concept. Intravaginally administered drugs might prevent infection at the portal of entry by inactivating the organism; blocking attachment of penetration; or interfering with specialized functions essential in disease pathogenesis. To facilitate development of prophylactic strategies for controlling STD we will pursue three specific aims: First, polysulfated carbohydrates and surface-active shown in Projects 1 and 2 to have minimal cell toxicity but potent in vitro activity against HSV and/or chlamydia will be studied to determine if they can protect guinea pigs against experimental genital infection. Intravaginal inoculation of guinea pigs with HSV or chlamydia results in infection remarkably similar to that observed in humans. These models have been useful in exploring microbial pathogenesis and should predict the efficacy of topical microbicides in women. Second, we will use HSV mutants engineered in Project 1 to explore aspects of the pathogenesis of genital herpes potentially important in the development of topical microbicides. Using mutants deficient in glycoprotein C (gC), a component of the viral envelope important for virion attachment, we will determine whether gC is important in the pathogenesis of genital infection. This information will establish whether gC is a potential target for microbicidal action. If intravaginal microbicide are to be effective in preventing genital herpes, they must block entry of virus into sensory neurons. Since nothing is currently known regarding how virus enters sensory nerves we will use gB and gD deficient mutants to examine whether HSV directly binds and penetrates sensory nerve endings or gains access via cell-to- cell spread from epithelial cells. Third, we will investigate the mechanism by which prophylactic treatment with a synthetic isomer of capsaicin, civamide, protects animals against genital herpes. Intravaginal capsaicin does not block viral replication nor directly inactivate HSV but appears to alter pathogenesis by interfering with specialized virus-neuron interactions. Even brief treatment with capsaicin results in a prolonged effect on the pathogenesis of genital herpes. Information gained from these experiments may allow development of new topically active neuropharmacological agents that will be effective in preventing genital HSV infection. Thus, the goals of our studies are to develop topical microbicides that warrant further evaluation in clinical trials and to examine aspects of the pathogenesis of genital herpes that might facilitate the rational development of intravaginal chemoprophylactic agents designed to prevent genital HSV infection.