TOPICAL THERAPY FOR HSV-2 INFECTION OF THE FEMALE GENITAL TRACT

女性生殖道 HSV-2 感染的局部治疗

• 批准号: 5205822
• 负责人: MARY K HOWETT
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5205822
• 关键词: DNA replication; SCID mouse; antiinfective agents; antiviral agents; athymic mouse; combination chemotherapy; disease /disorder model; drug screening /evaluation; genetic transcription; herpes simplex virus 2; histopathology; human papillomavirus; human tissue; keratinocyte; nonhuman therapy evaluation; regulatory gene; tissue /cell culture; topical drug application; vagina; virus infection mechanism; virus replication

Genital herpes virus infection is caused by infection of male or female genital tissues by herpes simplex virus type 2 (HSV-2) or less frequently by herpes simplex virus type 1 (HSV)-1). These two viruses have very similar structure, replication modes and a high degree of nucleic acid homology (50%); therefore, this proposal will focus on HSV-1. Genital herpes infection in the female can target the labial surfaces, the vagina and the cervix. Adjacent areas of buttock skin also may be infected. Infection may occur as a primary event, usually as a result of sexual transmission. As a consequence of primary infection, virus most often enters latency in sacral ganglia, and this latent virus can serve as a source of recurrent infection which is accompanied by replication of virus in skin, lesion formation and shedding of virus at skin surfaces. Primary infection is usually more severe, but recurrent infections may occur over a number of years and serve as a potent source of transmittable virus in the population. The incidence of this virus infection is extremely high with probably one-fourth of the population harboring HSV-2. Virtually all cells that have been examined are permissive for HSV-2 replication, although the natural targets are found in genital epithelial surfaces. Immunosuppressed patients are at grave risk for replication of this virus in all tissues and can suffer life-threatening sequelae from either primary or recurrent HSV-2 infection. The current mainstay of therapy for HSV-2 infection is Acyclovir, a potent nucleotide analogue specifically phosphorylated and incorporated into DNA in HSV-infected cells. Intravenous, oral and topical formulations of this compound have been shown to interdict virus replication and have therapeutic benefit. In addition, certain detergent based spermicides have proven anti-virucidal activity for HSV because it is an enveloped virus. Use of these virucides, with or without accompanying condom use, however, is not sufficiently prevalent in society to effectively halt virus transmission. The goals of this proposal will be; 1.) Measure HSV-2 immediate early (b) transcription and DNA replication and yield in TC-7 cells and in primary keratinocytes before and after exposure to anti-virucidal formulations. 2.) Productively infect human, vaginal xenografts with HSV-2. Define parameters of infection and examine histopathology of lesions. 3.) Use formulations of virucides that successfully interdict HSV-2 replication in Specific Aim 1 to alter outcome of standardized HSV-2 infection in the vaginal xenografts.

生殖器疱疹病毒感染是由男性或女性感染引起的 生殖器组织感染 2 型单纯疱疹病毒 (HSV-2) 或较少发生 1 型单纯疱疹病毒 (HSV)-1)。这两种病毒具有很强的 相似的结构、复制模式和高度的核酸 同源性（50%）；因此，本提案将重点关注HSV-1。生殖器 女性的疱疹感染可以针对阴唇表面、阴道 和子宫颈。臀部皮肤的邻近区域也可能被感染。 感染可能作为原发事件发生，通常是性行为的结果 传播。作为原发感染的结果，病毒最常 在骶神经节进入潜伏期，这种潜伏病毒可以作为 伴随病毒复制的反复感染源 在皮肤中，皮肤表面的病变形成和病毒脱落。基本的 感染通常更严重，但反复感染可能会发生 已存在多年，并成为传播病毒的有效来源 人口。这种病毒感染的发生率极高 可能有四分之一的人口携带 HSV-2。几乎所有 经过检查的细胞允许 HSV-2 复制， 尽管天然靶标存在于生殖器上皮表面。 免疫抑制患者面临这种病毒复制的严重风险 存在于所有组织中，并且可能遭受原发性或危及生命的后遗症 或复发性 HSV-2 感染。当前 HSV-2 的主要治疗方法 感染是阿昔洛韦，一种有效的核苷酸类似物 在 HSV 感染的细胞中磷酸化并整合到 DNA 中。 该化合物的静脉注射、口服和局部制剂已被证实 阻止病毒复制并具有治疗作用。此外， 某些基于清洁剂的杀精剂已被证明具有抗病毒活性 HSV 因为它是一种包膜病毒。使用这些杀病毒剂，与或 然而，在不使用安全套的情况下，这种现象在以下地区还不够普遍： 社会有效遏制病毒传播。本提案的目标 将; 1.) 测量 HSV-2 立即早期 (b) 转录和 DNA 复制 以及之前和之后 TC-7 细胞和原代角质形成细胞中的产量 接触抗病毒制剂。 2.) 用 HSV-2 有效感染人类阴道异种移植物。定义 感染参数并检查病变的组织病理学。 3.) 使用可成功阻断 HSV-2 的杀病毒剂制剂 在特定目标 1 中进行复制以改变标准化 HSV-2 的结果 阴道异种移植物感染。