**2.4 Endogenous retroviruses**

252 Endometriosis - Basic Concepts and Current Research Trends

The well-described human polyomaviruses of the *Polyomaviridae* family, JC (JCV), BK (BKV) and simian virus 40 (SV40) are widely distributed in the general population (Moens & Johannessen, 2008). Thus antibodies against JCV and BKV have been found in more than 75% of the human adult population, and up to 15% of healthy humans are seropositive for SV40. These three polyomaviruses have been found in many different tissues (see Vestergaard et al., 2010). BKV has been found in the kidney tubule epithelium, urethral epithelium, the uterine cervix, and in the spleen. JCV has been found in tongue squamous cell epithelium, urethral epithelium, and in the spleen, whereas SV40 has been found in the liver and the mesothelium. Furthermore, these three polyomaviruses induce tumours in animal models and are able to transform cultured human cells (Moens & Johannessen, 2008). In 2007, two new human polyomaviruses, WU polyomavirus (WUV) and KI polyomavirus (KIV) were discovered in respiratory tract secretions and have subsequently been detected in faeces, blood, and lymphoid tissue (see Vestergaard et al., 2010). The full spectrum of their tissue tropism and their role in disease has yet to be elucidated. More recently, yet another human member of the *Polyomaviridae* family, the Merkel cell polyomavirus (MCV) was described in apparent association with Merkel cell carcinoma, an aggressive form of skin cancer (Moens & Johannessen, 2008). When analysed, none of these polyomaviruses were detected either in the endometrium or in endometriosis, suggesting an infrequent

presence of polyomaviruses in the endometrium (Vestergaard et al., 2010).

and might not have any association with the endometriosis *per se*.

Closely related to the polyomavirus family, the papillomavirus family is a very significant example of the large impact of a broad spectrum of pathogenic DNA viruses, which have emerged during the last two decades. More than 118 papillomaviruses have been fully described, and new virus types are constantly emerging (zur Hausen, 2009). The prevalence of human papillomavirus (HPV, of the family *Papillomaviridae*) in cervical carcinomas is 99.7%. Specific high-risk HPV types have been shown to cause the vast majority of cervical cancers as well as a substantial proportion of other anogenital and head and neck cancers as well as certain cutaneous cancers. HPV has not yet been detected in intraperitoneal tissues, but HPV has been detected in blood, including on the surface of peripheral blood mononuclear cells, suggesting a potential alternative route of transmission (see Vestergaard

The prevalence of HPV in endometriosis has been analysed (Oppelt et al., 2010; Vestergaard et al., 2010). In one study, no HPV DNA was found in the endometriosis samples from 32 patients (Vestergaard et al., 2010). In another study, certain high-risk HPV types was found in endometriosis lesions (Oppelt et al., 2010). However, due to previous cervical HPV infections in the analysed patients, it was concluded that the detected HPV in the endometriosis samples possibly originated from these associated malignant transformations

In the endometrium, a HPV prevalence of less than 10% was found in samples from both women with endometriosis as well as controls, which is remarkably low compared with the well-known high frequencies of infection with these viruses (Vestergaard et al., 2010). It is

**2.2 Polyomaviruses** 

**2.3 Human papillomaviruses** 

et al., 2010).

Retroviruses are RNA viruses, which integrate into the genome of the host cell in the form of a DNA copy, which is denominated the provirus. Endogenous retroviruses refer to proviruses integrated into germ line cells, which are transmitted from one generation to the next. Approximately 5% of the human genome consists of complete and partial sequences from human endogenous retroviruses (HERVs) (Muir et al., 2004). The significance and consequences of the presence of HERVs in the human genome have been the subject of intensive investigation. HERVs have been implicated in autoimmune diseases and neoplasia as well as in placental function and protection from exogenous retroviral infection. Considering the placental function, it is now believed that syncytin, a retroviral envelope protein encoded by the endogenous retrovirus HERV-W, is involved in the fusion of the cytotrophoblast cells to form the syncytial layer of the placenta, and the envelope protein encoded by ERV3 has been associated with cytotrophoblast differentiation. Other endogenous retroviruses like HERV-E also seem to be involved in placental function (reviewed in Muir et al., 2004).

Expression of HERVs in endometriotic tissues has been detected, indicating that endogenous retrovirus expression might be involved in endometriosis (Hu et al., 2006; Oppelt et al., 2009). Endometriosis samples from 14 women were analysed for the presence of HERV-E HERV-W, HERV-I/T, and HERV-H mRNA by PCR analysis (Hu et al., 2006). It was found that HERV-E was expressed at higher levels in the endometriosis samples than in normal endometrium control samples. In another study, 15 endometriosis samples showed low levels of RNA encoding the HERV-W encoded envelope protein syncytin, as analysed by reverse transcriptase PCR (Oppelt et al., 2009). It was also found in this study that the endometriosis samples did not show an elevated expression of the HERV-W encoded envelope protein syncytin. Interestingly though, samples from the endometrium of women with endometriosis showed an increased expression of syncytin RNA compared with endometrial samples from controls, suggesting that this protein might be involved in the pathology of endometriosis. At this point, the involvement of endogenous virus expression in the pathology of endometriosis is not clarified. Further studies are required, analysing larger groups of endometriosis samples and including tissue samples from the endometrium of women with and without endometriosis.
