p53, WAF1/CIP1 and mdm2 expression in skin lesions associated with human papillomavirus and human immunodeficiency virus

Abstract

Human papillomaviruses (HPVs) express various gene products, such as E6 protein which complexes with the p53 tumor suppressor protein and therefore diminishes p53-related regulatory mechanisms. This interaction is assumed to be HPV type-specific as "high risk" or oncogenic HPV types have more affinity for p53 binding than their "low risk" or non-oncogenic counterparts. Furthermore, HIV infection is believed to activate latent HPV infection and transcription via direct and indirect interaction with HPVs as well as cellular genes and functions. Accordingly, we carried out experiments on biopsies which originated from condylomas ("low risk" HPVs), HIV-positive condylomas (infection with multiple "low risk" and "high risk" HPVs) and anogenital squamous cell carcinomas (SCCs, "high risk" HPV infection). Using reverse transcription PCR (RT-PCR) and western immunoblotting, mRNA and protein levels of p53 and genes regulated by p53, such as mdm2 and WAF1/CIP1 were determined. We found that the presence of HPV can diminish p53 and increase WAF1/CIP1 and mdm2 protein levels. There were no significant differences in this regulation between "low risk" and "high risk" lesions. Our data suggest that these HPV-mediated cellular effects are not type-specific, and they might be part of a viral-cell interaction or represent a cellular defense mechanism against the virus. However, HIV-seropositivity renders HPV lesions containing both "low risk" and "high risk" significantly different. This may be due to the alteration of HPV-controlling cellular pathways by HIV tat and/or activation of cellular pathways different from HIV-negative counterparts. Either possibility is of great interest and needs further verification.