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

生殖器疱疹病毒感染是由男性或女性感染引起的

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.