Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins

Abstract

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated.

High-Risk Human Papillomavirus and Epstein–Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis

“…Both HPV and EBV demonstrate a broad range of mechanisms to evade both the innate and adaptive antiviral host response for virus replication (reviewed in [ 150 , 151 ]). Interestingly, some mechanisms of immune evasion in HPV infection are also used by EBV.…”

Dangerous Liaisons: Long-Term Replication with an Extrachromosomal HPV Genome

“…In addition to the evasion tactics described above, the E5, E6, and E7 proteins inhibit detection of viral DNA by interfering with foreign DNA sensors, cytokine production, and interferon signaling pathways [ 91 , 92 , 93 ]. Therefore, the genomes of persistently infected cells replicate alongside viral DNA that would be normally eliminated from the cells.…”

Pathogenic Role of Immune Evasion and Integration of Human Papillomavirus in Oropharyngeal Cancer

“…The innate immune response is the first line of host defense against pathogens, including HPV. To detect and respond to pathogens, most cells of the innate immune system express pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. TLR9 acts as a sensor by recognizing unmethylated double-stranded DNA CpG motifs present in the genome of viruses, such as HPVs [ 37 ].…”