Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism

Abstract

A persistent infection with the so-called high-risk Human Papillomaviruses (hr-HPVs) plays a fundamental role in the development of different neoplasms. The expression of the HPV proteins throughout the different steps of the viral life cycle produce a disruption of several cellular processes, including immune response, which can lead to cell transformation. The interferon-mediated response plays an important role in eliminating HPV-infected and -transformed cells. The ability of HPV to disrupt the proper function of the interferon response is based on a series of molecular mechanisms coordinated by HPV proteins intended to prevent clearance of infection, ultimately producing an immunotolerant environment that facilitates the establishment of persistence and cancer. In this review, we focus on the molecular actions performed by HPV E1, E2, E5, E6 and E7 proteins on IFN signaling elements and their contribution to the establishment of infection, viral persistence and the progression to cancer.

Molecular aspects of cervical cancer: a pathogenesis update

“…The determinants of HR-HPV persistent infections are not precise. Still, they may be related to the inability of the host to mount an adequate innate immune response and a robust cell-mediated immunity, as well as the ability of the viral proteins to evade immune detection ( 20 – 22 ). Although only 0.6% of HPV infections are known to progress to cancer, a 16-year follow-up study has shown that the risk of developing cancer is 75.4 times higher in women with persistent HR-HPV infections compared to HPV-negative women ( 23 ).…”

Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities

“…For instance, chemically derived Imiquimod is an immunomodulatory dosage that affects both the innate and adaptive immune responses and the activation of natural killer cells, the production and release of interferon (IFN)-alpha, tumor necrosis factor-alpha, and interleukin-12, in addition to the suppression of viral replication. 240 Cidofovir is another nucleotide analogue that works by inhibiting viral DNA polymerase, and the medication cidofovir also helps to reduce the HPV-positive tumor cells' propensity for metastasis. 241 Other chemically derived antivirals, such as Ganciclovir, Acyclovir, and Famciclovir, target the viral DNA of the Epstein−Bar virus during the infection stage, thus preventing its progression along with the inhibition of host cell DNA polymerase (Figure 4).…”

“…Next, the potential of human papillomavirus to interfere with the proper functioning of the interferon response based on several molecular pathways coordinated by human papillomavirus proteins aimed to prevent infection clearance results in the creation of an immunotolerant environment that promotes the establishment of persistence and cancer. For instance, chemically derived Imiquimod is an immunomodulatory dosage that affects both the innate and adaptive immune responses and the activation of natural killer cells, the production and release of interferon (IFN)-alpha, tumor necrosis factor-alpha, and interleukin-12, in addition to the suppression of viral replication . Cidofovir is another nucleotide analogue that works by inhibiting viral DNA polymerase, and the medication cidofovir also helps to reduce the HPV-positive tumor cells’ propensity for metastasis .…”

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy

“…E6 also contributes to the downregulation of the immune response against HPV by suppressing IFR3 (Interferon Regulatory Factor 3), a transcription factor for interferons (IFNs) ( 132 , 133 ), and by inhibiting IFNA (interferon alpha) interaction with its receptor ( 134 ). E7 acts synergically by inhibiting TLR9/CD289 (Toll-like receptor-9), present intracellularly in several immune cell types ( 135 , 136 ).…”