Manifestations of HPV in transplant patients

Abstract

S13 Iatrogenic systemic and topical immunosuppression is maintained for a wide range of clinical problems, particularly prolonged and profound in transplant recipients. The consequences of such treatment are becoming apparent with increasing time from transplantation. Recent interest has focused on a 50-100 fold increased risk of cutaneous and mucosal squamous cell carcinomas (SCC) ranging from 12-95% long term survivors, dependent on geographical location. 90% of long term renal transplant recipients (RTRs) have mucocutaneous warts and the observed clinicopathological progression through dysplastic keratoses to frank tumours has prompted a search for the involvement of Human Papillomaviruses (HPVs). In contrast to anogenital cancers where oncogenic mucosal HPVs 16/18 (and related viruses) are clearly implicated and the genodermatosis epidermodysplasia verruciformis (EV) where EV-HPVs (HPV5,8 and related viruses) are found, historical studies of RTR SCCs have shown inconsistent results. Recent studies using degenerate PCR techniques have shown a high prevalence (65-80%) of HPV DNA in lesions from RTRs. Our group has designed a comprehensive and sensitive HPV detection and genotyping method employing a panel of degenerate and nested primers capable of detecting a broad range of cutaneous, mucosal and EV HPVs. HPV can be detected in 95% viral warts, 80% SCCs and 95% of dysplastic lesions from RTRs and also in tumours from patients receiving PUVA. The spectrum of HPVs is broadly similar for all lesions: EV and cutaneous HPVs are found more frequently than mucosal HPVs and are often codetected. Multiple novel EV related HPVs genotypes have been identified. In an attempt to define a role for these HPVs we have focused on one novel HPV type (HPV77) which appears restricted to RTRs. We show that HPV77 gene transcription is activated in cells following UV irradiation and this is mediated through binding of the p53 tumour suppressor protein to viral regulatory sequences. This is the first identification of a p53 responsive element within a viral genome, and suggests novel mechanisms by which HPV and UV radiation might act as cofactors in cutaneous carcinogenesis. Most significantly, analysis of a common polymorphic variant of p53 revealed striking differences in the susceptibility of p53 inactivation by the HPV E6 protein. Further results suggest that p53 polymorphic variants are a genetic determinant of susceptibility to the development of HPV associated cutaneous and cervical cancers. Long term survival of patients with AIDS may increase the prevalence of HPV associated tumours in mucocutaneous sites. A comprehensive screening for unusual HPVs is required for their detection and an analysis of p53 polymorphisms relevant. Novel treatment approaches to HPVs and the use of systemic retinoids may become relevant to the management of AIDS.