HPV: from infection to cancer

Abstract

Infection with HPV (human papillomavirus) 16 is the cause of 50% or more of cervical cancers in women. HPV16 infection, however, is very common in young sexually active women, but the majority mount an effective immune response and clear infection. Approx. 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections, since the infectious cycle is one in which viral replication and release is not associated with inflammation. Furthermore, HPV infections disrupt cytokine expression and signalling with the E6 and E7 oncoproteins particularly targeting the type I IFN (interferon) pathway. High doses of IFN can overcome the HPV-mediated abrogation of signalling, and this may be the basis for the therapeutic effects on HPV infections of immune-response modulators such as the imidazoquinolones that induce high levels of type I IFNs by activation of TLR (Toll-like receptor) 7. Using the unique W12 model of cervical carcinogenesis, some of these IFN-related interactions and their relevance in the selection of cells with integrated viral DNA in cancer progression have been investigated. Our data show that episome loss associated with induction of antiviral response genes is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. Exogenous IFN-beta treatment of W12 keratinocytes in which the majority of the population contain episomes results only in the rapid emergence of IFN-resistant cells, loss of episome-containing cells and a selection of cells containing integrated HPV16 in which the expression of the transcriptional repressor E2 is down-regulated, but in which E6 and E7 are up-regulated.

TLR9 Expression in Uterine Cervical Lesions of Uyghur Women Correlate with Cervical Cancer Progression and Selective Silencing of Human Papillomavirus 16 E6 and E7 Oncoproteins in Vitro

“…They can promote the transforma-tion of the infected cell by altering the regulation of fundamental cellular events, such as apoptosis and the cell cycle. The E6 and E7 oncoproteins exert their functions by inducing the degradation of two important tumor suppressors, p53 and retino-blastoma (pRb), respectively, and cooperates with each other to immortalize primary keratinocytes (Stanley et al, 2007). However, Hasan UA (Hasan et al, 2007) found that TLR9 expression and function also was abolished by the cervical cancer-associated human papillomavirus type 16.…”

DNA-tumor virus entry—From plasma membrane to the nucleus

“…In certain primary cells or explant cultures, they have been more difficult to study due to strong innate host anti-virus responses, and the limited availability and batch-to-batch variations of these cells. Nonetheless, there are a number of entry steps that are universally required for infection of diverse cell types with human or prototypic DNA-tumor viruses, including virus attachment to a receptor at the cell surface (for recent reviews, see 34,[35][36][37][38][39][40], and lateral movements of the virus-receptor complex to specialized sites on the plasma membrane (reviewed in 41,42). These lateral movements can lead the virus particles, for example, to tight and adherens junctions, where additional receptors are localized, such as CAR for adenoviruses, or nectins for herpesviruses (34).…”

Inflammatory pathways in cervical cancer – the UCT contribution

“…4 The HPV genome consists of 3 domains, a non-coding upstream region, an early region containing open reading frames E1, E2, E4, E5, E6 and E7, and a late region encoding the major and minor capsid proteins. 4 In the vast majority of women, infections and HPV-induced lesions are transient and are naturally resolved. However, approximately 10 -20% of women fail to eliminate the virus.…”

“…However, approximately 10 -20% of women fail to eliminate the virus. 4 In these cases, persistence of infection, viral integration and activation of inflammatory pathways have been linked to neoplastic transformation and malignant progression. 4,5 In this review, we highlight our findings relating to the activation of inflammatory pathways in cervical cancers and address their role in disease progression.…”