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 生殖器组织感染单纯疱疹病毒2型(HSV-2)或更少 由单纯疱疹病毒1型(HSV)-1感染)。这两种病毒有很强的 结构相似，复制方式相似，核酸含量高 同源性(50%)；因此，这项建议将集中在HSV-1上。生殖器 女性的疱疹病毒感染可以针对唇部表面、阴道 还有宫颈。臀部皮肤的邻近区域也可能受到感染。 感染可作为主要事件发生，通常是由于性行为 变速箱。作为初次感染的结果，病毒最常见的是 进入骶神经节的潜伏期，这种潜伏的病毒可以作为 伴随病毒复制而复发的感染源 在皮肤中，皮损形成和病毒在皮肤表面脱落。主要 感染通常更严重，但可能会发生反复感染。 多年来一直是可传播病毒的一个重要来源 人口数量。这种病毒感染的发生率极高。 大约四分之一的人口携带HSV-2。几乎所有的 已经检查的细胞允许HSV-2复制， 虽然天然靶标是在生殖器上皮表面发现的。 免疫抑制的患者面临这种病毒复制的严重风险。 在所有组织中都有，并可能遭受威胁生命的后遗症 或复发的HSV-2感染。目前治疗单纯疱疹病毒2型的主流药物 感染是阿昔洛韦，一种特别有效的核苷酸类似物 在单纯疱疹病毒感染细胞中被磷酸化并并入DNA。 这种化合物的静脉注射、口服和外用制剂已经被展示出来。 阻断病毒复制，具有治疗作用。此外, 某些以洗涤剂为基础的杀精剂已被证明具有抗病毒活性 单纯疱疹病毒，因为它是一种包膜病毒。使用这些病毒杀菌剂，与或 然而，在没有使用避孕套的情况下， 社会有效阻止病毒传播。这项提案的目标是 将会是； 1)检测HSV-2即刻早期(B)转录和DNA复制 治疗前后TC-7细胞和原代角质形成细胞的产率 暴露在抗病毒配方中。 2.)用HSV-2高效感染人和阴道移植瘤。定义 感染参数，并检查病变的组织病理学。 3.)使用成功阻断HSV-2的病毒制剂 针对特定目标1的复制改变标准化HSV-2的结果 异种阴道移植物的感染。