TOPICAL THERAPY FOR HSV-2 INFECTION OF THE GENITAL TRACT

生殖道 HSV-2 感染的局部治疗

基本信息

批准号：
6352611
负责人：
Mary K. Katherine Howett
金额：
$ 5.82万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2001-08-31
项目状态：
已结题

项目摘要

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). This proposal will focus on HSV-2. 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. Following primary infection, virus most often enters latency in sacral ganglia and can serve as a source of recurrent infection. 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. Incidence of this virus infection is extremely high. Immunosuppressed patients are at grave risk for replication of this virus at all tissues and can suffer life-threatening sequelae. 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 therapeutic benefit. In addition, certain detergent based spermicides have proven anti-virucidal activity for HSV. Studies in the previous three years of this Program Project have shown that C31G (C14/C16) and an alkyl sulfate microbicide can each inactivate HSV-2. Importantly, SDS has been shown to prevent HSV-2 infection in an in vivo model of infection in the mouse vaginal and SDS and C31G have been shown to inactivate HSV-2 and prevent infection in a human vaginal xenograft model. Our specific aims in the next phase of this grant will include: 1) continue to employ three model systems for HSV-2 growth to determine the toxicity and efficacy of non-formulated and formulated microbicidal compounds: a) in vitro assay of HSV-2 by plaque formation in monkey kidney epithelial cells and primary human vaginal keratinocytes; b) in vivo assay by vaginal inoculation of Swiss-Webster, outbred mice, c) in vivo assay by inoculation of human, vaginal xenografts growing in immunocompromised mice; 2) compare the kinetics and natural history of HSV-2 infection following inoculation of either normal, human, vaginal xenografts or human vaginal xenografts expressing the complete repertoire of viral genes from HPV-11; and 3) determine if acute of subclinical HSV-2 infection of human vaginal xenografts growing in nude mice, SCID mice or SCID mice that have been reconstituted with human lymphoreticular cells, alters the complexity of cells in the xenografts that serve as potential targets for HIV infection.

生殖器疱疹病毒感染是由男性或女性生殖组织感染 2 型单纯疱疹病毒 (HSV-2) 或少数情况下感染 1 型单纯疱疹病毒 (HSV-1) 引起的。该提案将重点关注 HSV-2。女性感染可针对阴唇表面、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，通常是性传播的结果。原发感染后，病毒最常在骶神经节中潜伏，并可作为复发感染的来源。原发感染通常更为严重，但复发性感染可能会在数年内发生，并成为可传播病毒的有效来源。这种病毒感染的发生率极高。免疫抑制的患者面临这种病毒在所有组织中复制的严重风险，并可能遭受危及生命的后遗症。目前 HSV-2 感染的主要治疗方法是阿昔洛韦，它是一种有效的核苷酸类似物，在 HSV 感染的细胞中被特异性磷酸化并整合到 DNA 中。该化合物的静脉、口服和局部制剂具有治疗益处。此外，某些基于清洁剂的杀精剂已被证明具有针对 HSV 的抗病毒活性。该项目前三年的研究表明，C31G (C14/C16) 和烷基硫酸盐杀菌剂均可灭活 HSV-2。重要的是，SDS 已被证明可以在小鼠阴道感染的体内模型中预防 HSV-2 感染，并且 SDS 和 C31G 已被证明可以灭活 HSV-2 并预防人阴道异种移植模型中的感染。我们下一阶段拨款的具体目标包括：1) 继续采用三种 HSV-2 生长模型系统来确定非配制和配制杀菌化合物的毒性和功效：a) HSV-2 的体外测定通过猴肾上皮细胞和原代人阴道角质形成细胞中的斑块形成； b)通过对Swiss-Webster远交小鼠进行阴道接种进行体内测定，c)通过对在免疫功能低下的小鼠中生长的人阴道异种移植物进行接种进行体内测定； 2) 比较接种正常人阴道异种移植物或表达 HPV-11 病毒基因完整库的人阴道异种移植物后 HSV-2 感染的动力学和自然史； 3) 确定在裸鼠、SCID 小鼠或用人淋巴网状细胞重建的 SCID 小鼠中生长的人阴道异种移植物的急性或亚临床 HSV-2 感染是否会改变异种移植物中作为 HIV 潜在靶标的细胞的复杂性感染。