Model systems for human papillomavirus production and virus interactions with herpes simplex virus type two: Implications for cervical cancer

Infection with a high-risk type HPV constitutes the major risk factor for developing cervical cancer. However, it is clear that HPV is not sufficient for full malignant transformation. Patients infected with HPV do not necessarily develop cervical cancer, indicating that other risk factors and events are involved. Recent epidemiological studies found that women infected with both herpes simplex virus type 2 (HSV-2) and HPV 16 or 18 are at greater risk of developing cervical carcinoma compared to women infected with only one type of virus. In vitro studies indicated that HSV-2 transforming domains promoted progression of HPV-immortalized human cells to a tumorigenic phenotype. However, it remains unclear if HSV-2 is a cofactor and if HPV and HSV-2 interact in anyway for the development of cervical cancer. Using an in vitro HPV11 and HSV-2 co-infection assay, we have demonstrated that HSV-2 infection resulted in down regulation of HPV transcripts in a non-sequence and cell type specific manner.; In summary, we have demonstrated that HSV-2 infection resulted in suppression of HPV transcripts in a non-sequence and cell type specific manner. The suppression of HPV transcripts by HSV-2 infection applied to both high-risk and low-risk types of HPV and is an apparent result of the virion derived HSV-2 vhs function. Coinfection of HPV and HSV-2 can clearly exist in a same tissue in vivo in the vaginal epithelial xenograft model. HSV-2 infection resulted in classical cytopathic effect with tissue destruction and inhibition of HPV activities in areas of HPV11 inducted papillomas. These studies may lead to therapeutic applications for HPV infections and related neoplasms by utilizing targeted delivery of vhs to down regulate HPV macromolecules and also may lead to the development of HSV-2 as an oncolytic agent for the treatment of cervical cancer. We also demonstrated that the induction of productive stage of HPV11 viral life cycle in N-tert cells grown in raft culture starting from HPV11 DNA. This will facilitate further study of the HPV11 viral life cycle and gene functions by genetic manipulation of the HPV genome and allow comparison of the life cycle of low and high-risk types of HPV. Finally, we also demonstrated the feasibility of using baculovirus mediated high efficiency gene delivery to primary keratinocytes, and this will facilitate the continued effort for production of HPV16 and further study of HPV gene functions. (Abstract shortened by UMI.)...