For optimal control and clearance of HPV infections, both the innate and adaptive arms of the immune response appear to be critical. As described, HPV modulates a series of cellular pathways to evade host immune responses during persistent infection. Some of these mechanisms may lead to virus-mediated immune suppression that creates an immunosuppressive microenvironment in mucosal epithelia, which is vital for cancer progression. Recent clinical trials of novel immunotherapies have promise as cancer therapeutics by reversing tumor-induced immune suppression; however, a majority of treated patients generally do not respond to immune checkpoint inhibitors (Gildener-Leapman et al., 2013; Hamid et al., 2013; Wolchok et al., 2013). Thus, it is very likely that there are additional mechanisms by which tumor glycine receptors evade antitumor immune responses. As described above, HPV manipulates various molecular and cellular pathways in host cells to evade host immune surveillance and antiviral immune responses. HPV-mediated immune suppression during virus persistence might also contribute to tumor cell evasion of antitumor immune responses. Thus, an in-depth understanding of the mechanisms of HPV-associated immune evasion potentially lead to the development of novel immunotherapeutic tools that effectively restore antiviral and antitumoral immune responses.
This work was supported by the National Institutes of Health (grant numbers R01 AI091968 and R01 DE026125), Mary Kay Foundation, Dallas, TX (grant number 041-15), The Colorado Clinical and Translational Sciences Institute, and Cancer League of Colorado (grant number 163354-DP).
Papillomaviruses comprise an ancient and ubiquitous virus family that infects humans and other animals (Bravo and Félez-Sánchez, 2015). Human papillomaviruses comprise the largest group of papillomaviruses. There are over 200 different HPV genotypes identified to date based on full genome sequencing (2012). The majority of HPV subtypes are classified under the alpha- and beta-HPV groups while a few other HPV subtypes have been classified under the gamma, mu and nu genera (Bernard et al., 2010; de Villiers et al., 2004). In general, alpha HPVs infect mucosal epithelia while beta HPVs infect external cutaneous epithelia. HPV infection causes a range of benign conditions such as condyloma acuminata (genital warts), focal epithelial hyperplasia, common warts, plantar warts and pigmented warts (Cubie, 2013; Doorbar et al., 2015). Infection with HPV is usually transient and the majority of infections are cleared by the immune system (Stanley, 2012). However, in the case of some HPVs, if infection becomes persistent this may lead to tumour progression (Bodily and Laimins, 2011). Around forty alpha HPVs infect the anogenital epithelium. Of these, up to fifteen genotypes are so-called “high-risk” HPVs (HR-HPVs) because they are associated with a range of cancers including cervical and other anogenital cancers and oropharyngeal cancers (Cubie, 2013). HPV type 16 is the most prevalent HR-HPV responsible for 55% of cervical cancers. After chlamydia, it is the second most prevalent sexually transmitted infectious agent worldwide. In the developed world the incidence of certain anogenital and oropharyngeal cancers has increased significantly over the last decade (Gillison et al., 2015). Thus, the medical importance of HPV is clear. Vaccines against HPV16 and HPV18, the next most prevalent HR-HPV and the genital wart-causing, non-oncogenic HPVs 6 and 11, have been available for eight years. However, these are prophylactic and cannot protect the very large numbers of people worldwide who are already infected and at risk of serious disease. Understanding viral gene regulation and its relationship to the infected epithelium is a key goal to allow development of novel antiviral strategies in future.