How can HPV E6 manipulate host cell differentiation process to maintain the reservoir of infection
Yuwen Chen, Nagayasu Egawa, Ke Zheng, John Doorbar
Abstract
Human papillomavirus (HPV) is a DNA virus that infects the skin and mucous membranes, playing a significant role in the development of various cancers, including cervical cancer, anogenital cancers and oropharyngeal cancer. There are over 200 types of HPV, categorised into low-risk and high-risk types based on their potential to cause cancer [1]. Nearly all cases (95 %) of cervical cancer are associated with persistent high-risk HPV infection. Overall, 4.5 % of all cancer cases worldwide are attributed to HPV [2]. HPVs are categorised as low- or high-risk based on their oncogenic potential, which is largely driven by differences in their E6 and E7 viral proteins. During the natural course of HPV infections, HPV remains as an episome and integration into the host genome is an infrequent occurrence and is not essential for the virus to complete its productive life cycle or replicate. When the expression of E6 and E7 remain regulated, these proteins function primarily to modulate the host cell cycle, facilitating the persistence of the viral genome. They are referred to as oncogenes only when their expression becomes deregulated. High-risk HPVs, such as HPV-16 and HPV-18, encode E6 and E7 proteins that bind strongly to and degrade critical tumor suppressors, including p53 and retinoblastoma protein (pRb), thereby bypassing cell cycle control to proliferate and promoting mutations that contribute to cancer progression. This interference with p53 and pRb also disrupts DNA repair pathways, heightening genomic instability and establishing a cellular environment conducive to viral DNA integration into the host genome, further accelerates oncogenic transformation by uncontrollable oncoprotein expression [3]. NHERF1, on the other hand, is targeted by both high-risk and low-risk HPV E6 proteins, as well as E6 from diverse animal papillomaviruses. This suggests that NHERF1 has a broader impact on epithelial growth, which can lead to both benign and malignant outcomes depending on other viral and host factors [4].