**3. HPV**

Papillomaviruses are a family of pathogens that infect exclusively the epithelial tissues of amphibians, reptiles, birds and mammals (Franceschi, 2005). The viruses are grouped accord‐ ing to the anatomic site of infection and their preference for either cutaneous or mucosal squamous epithelium. The cutaneous types, or beta papillomaviruses, are usually found in the general population and cause common warts. In contrast, the alpha, or mucosotropic, papil‐ lomaviruses have been implicated in mucosal infections (Snow & Laudadio, 2010; Vidal & Gillison, 2008). The mucosotropic group of human papillomavirus comprises 15 species and infects the anogenital tract, upper aerodigestive tract and other head and neck mucosa (Chow et al., 2010). Because they are sexually transmitted and play important roles in diseases, these viruses have received much attention and research and clinical investment (Chow et al., 2010).

As molecular virology is depicted in details in another chapter, here we will only cover penile cancer-related aspects. Currently, over 200 HPV genotypes have been identified (Wang et al., 2012). HPVs with a high affinity for mucosal sites can be classified into non-oncogenic, or lowrisk, types or as potentially oncogenic, or high-risk, types. Mucosal and genital HPVs can be divided into low-risk (HPVs 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81) and high-risk (HPVs 16, 18, 31, 33, 35, 51, 52) types according to their presence in malignant lesions (Bosch et al., 2002; Muñoz et al., 2003).

The multiplicity of functions of the small papillomavirus oncoproteins, E5, E6 and E7, continues to be studied through last decades, although there are several mechanisms well established. Specifically, more than a dozen protein-protein interactions between E6 and cellular proteins have been shown (Villa et al., 2002). Taken into a carcinogenic point of view, E6 and E7 ORF are considered to play the most important roles, encoding for oncoproteins that allow viral replication and the immortalization and transformation of the epithelial cell that host the HPV DNA (Doorbar et al., 1991).

Proving the importance of p53 and pRb in cell cycle progression, the repression of HPV 16 E6 and E7 expression by dual shRNA transfection has been shown to be capable of restoring the p53 and pRb tumor suppressor pathways and activating apoptosis (Psyrri et al., 2009, Rampias et al., 2009). Thus, the demonstration of this tumor suppressor inactivation by the E6 and E7 HPV oncoproteins has provided a basic explanation for how the high-risk HPV types exert their oncogenic effects on cervical cells, and this explanation are under investigation to be related with other sites of HPV-infection. This is particularly important in penile cancerassociated HPV infection, whereas HPV16 seems to develop a pivotal role, and accounts for more than 60% of HPV-related tumors.
