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: 3727793
• 负责人: MARY K HOWETT
• 金额: --
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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/3727793
• 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 生殖器组织单纯疱疹病毒2型（HSV-2）或更少 单纯疱疹病毒1型（HSV）-1）。这两种病毒具有非常 相似结构、复制模式和高度核酸 同源性（50%）;因此，该建议将集中于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，通常是由于性行为。 传输作为初次感染的结果，病毒最常 进入骶神经节潜伏期，这种潜伏病毒可以作为一种 伴随病毒复制的反复感染源 在皮肤中，在皮肤表面形成损伤和脱落病毒。初级 感染通常更严重，但复发性感染可能发生在 多年来，作为一个强大的来源，可传播的病毒， 人口。这种病毒感染的发病率极高 可能有四分之一的人口携带HSV-2。几乎所有 已经检测的细胞允许HSV-2复制， 尽管天然靶点存在于生殖器上皮表面。 免疫抑制的患者有很大的风险复制这种病毒 在所有组织中，并且可能遭受危及生命的后遗症， 或复发性HSV-2感染。目前治疗HSV-2的主要方法是 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掺入DNA中。 该化合物的静脉、口服和局部制剂已被证明是 阻断病毒复制并具有治疗效果。此外，本发明还提供了一种方法， 某些基于去污剂的杀精子剂已被证明具有抗病毒活性 因为它是一种有包膜的病毒。这些杀病毒剂与或 然而，如果不使用避孕套， 有效遏制病毒传播。本提案的目标 将是; 1.）的人。测量HSV-2即刻早期（B）转录和DNA复制 在TC-7细胞和原代角质形成细胞中， 接触抗病毒制剂。 2.）的情况。用HSV-2有效感染人阴道异种移植物。定义 感染参数和检查病变的组织病理学。 3.）第三章使用成功阻断HSV-2的杀病毒剂制剂 在特异性目标1中复制以改变标准化HSV-2的结果 阴道异种移植物感染