Suppression of human papillomavirus gene expression in vitro and in vivo by herpes simplex virus type 2 infection.

Recent epidemiological studies have found that women infected with both herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) type 16 or HPV-18 are at greater risk of developing cervical carcinoma compared to women infected with only one virus. However, it remains unclear if HSV-2 is a cofactor for cervical cancer or if HPV and HSV-2 interact in any way. We have studied the effect of HSV-2 infection on HPV-11 gene expression in an in vitro double-infection assay. HPV transcripts were down-regulated in response to HSV-2 infection. Two HSV-2 vhs mutants failed to reduce HPV-16 E1;E4 transcripts. We also studied the effect of HSV-2 infection on preexisting experimental papillomas in a vaginal epithelial xenograft model. Doubly infected grafts demonstrated papillomatous transformation and the classical cytopathic effect from HSV-2 infection. HPV and HSV DNA signals were mutually exclusive. These studies may have therapeutic applications for HPV infections and related neoplasms.

A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses.

Sodium dodecyl sulfate (SDS), an alkyl sulfate surfactant derived from an organic alcohol, possesses surfactant properties but also denatures and unfolds both monomeric and subunit proteins. In preliminary experiments, we demonstrated that SDS is a potent inactivator of herpes simplex virus type 2 and human immunodeficiency virus type 1 at concentrations comparable to those used for the surfactant nonoxynol-9. We hypothesized that SDS might be capable of denaturing the capsid proteins of nonenveloped viruses. In this report, we demonstrate inactivation of rabbit, bovine, and human papillomaviruses after brief treatment with dilute solutions of SDS. Effective concentrations were nontoxic to rabbit skin and to split-thickness grafts of human foreskin epithelium. This is the first report of a microbicidal surfactant that will inactivate papillomaviruses. We propose that SDS is now a candidate microbicide for formulation and testing with humans.

Correlation of TGF beta 1 overexpression with down-regulation of proliferation-inducing molecules in HPV-11 transformed human tissue xenografts.

The epidemiologic association of human papillomavirus (HPV) infection with dysplasia and cervical cancer is well established. Transforming growth factor beta 1 (TGF beta 1) has regulatory effects on a broad spectrum of cell types and is a growth inhibitory protein for epithelial cells. To examine the phenotype of experimentally generated, HPV-11 transformed human tissues, we looked at expression of TGF beta 1 and a number of proliferation-enhancing molecules which are known to be regulated by TGF beta 1, including bcl-2, c-myc, c-Ha-ras, c-jun and NFkB. HPV-11 transformed xenografts showed up-regulation of TGF beta 1 expression and down-regulation of the expression levels of bcl-2, c-myc, c-Ha-ras, c-jun and NFkB. These results suggest that TGF beta 1 may exert antiproliferative effects on HPV-11 transformed papillomas by down-regulating different proliferation-enhancing molecules.

Transforming growth factor beta 1 (TGF beta 1) down-regulates expression and function of proliferation-inducing molecules in HPV-transformed cells.

The epidemiologic association of human papillomavirus (HPV) infection with dysplasia and cervical cancer is well established. Transforming growth factor beta 1 (TGF beta 1) is a growth inhibitory protein for epithelial cells. To examine the phenotype of HPV-transformed cells, we examined expression of TGF beta 1 and a number of cellular proliferation-enhancing molecules which are known to be regulated by TGF beta 1, including bcl-2, c-jun and NFkB. Previous studies had identified significant induction of TGF beta 1 and concomitant down-regulation of other growth stimulatory molecules in experimental papillomas. We used HPV-16 and -18 transformed cell lines. The HPV-16 transformed cells showed down-regulation of bcl-2 and NFkB as well as NFkB function upon TGF beta 1 treatment. The results suggest that TGF beta 1 may exert antiproliferative effects on some HPV-transformed cells by down-regulating expression and function of different proliferation-enhancing molecules. It is uncertain if this function is virus type specific and/or related to state of tumor cell progression.

Localization of protein kinase C alpha isoform expression in the human gastrointestinal tract.

Protein kinase C (PKC) includes a family of related proteins which constitutes a major signal transduction pathway. The aim of this study was to determine the localization of the PKC-alpha isoform throughout the human gastrointestinal tract. PKC-alpha expression was also measured and compared between normal and neoplastic colorectal tissue. PKC-alpha mRNA expression was detected in normal human gastrointestinal tract tissue using Northern blot analyses and in situ hybridization. PKC-alpha protein expression was detected in normal gastrointestinal tissue and colorectal neoplasia using Western blot and immunohistochemical analyses. PKC-alpha was expressed throughout the human gastrointestinal tract. Distinct organ and cellular localization was characterized. PKC-alpha mRNA and protein localization were most prevalent in the deep basal layer of the esophageal mucosa. In the stomach, PKC-alpha expression was detected predominately in the cells of the deep glands and surface epithelial cells but less in the mucous neck cells of the gastric pits. In the duodenum and ileum, PKC-alpha mRNA expression was greater in the deeper crypt cells than in the differentiated cells that line the villi. However, immunohistochemistry showed greater expression in the cells of the villi compared to crypt cells. In normal colonic tissue, PKC-alpha mRNA and protein predominated in the cells of the upper crypt and surface epithelial cells. PKC-alpha protein was also prominently expressed in the glands of colorectal adenocarcinoma. There was no quantitative difference in the level of PKC-alpha protein expression between normal and neoplastic colorectal tissue. The specific organ and cellular expression of PKC-alpha suggests separate and distinct functional roles for this PKC isoform throughout the gastrointestinal tissues.