The innate immune response is the first line of defense against microbial pathogens. To detect and respond to the invading pathogens, cells utilize specialized receptor proteins, defined as pattern recognition receptors (PRRs), which bind to pathogen-associated molecular patterns (PAMPs), a set of viral proteins and nucleic acids, including double-stranded RNA, single-stranded RNA, CpG unmethylated DNA and 5′ triphosphorylated RNA (ppp-RNA) [34,35,36,37,38,39,40,41,42,43,44].

Based on their location, PRRs are classified as membrane-bound or unbound intracellular receptors. The former comprises Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which are located at the surface of cells or endocytic compartments. The latter includes leucine-rich repeat (LRR)-containing (or NOD-like) receptors (NLRs), RIG-I-like receptors (RLRs) and the AIM2-like receptors (ALRs), which are located in the cytoplasm to sense intracellular pathogens. Furthermore, a panel of structurally unrelated cytosolic DNA sensors has been identified, among which the most relevant is the enzyme cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP–AMP) synthase (cGAS), which in bound conformation with double-stranded DNA (dsDNA) catalyzes adenosine 5′-triphosphate (ATP) and guanosine 5′-triphosphate (GTP) into cyclic GMP–AMP (2′3′-cGAMP). This second messenger binds to and activates the stimulator of interferon genes (STING), a scaffold protein localized on the endoplasmic reticulum (ER) membrane. Although PRRs are different in terms of structure, the point of sensing and adaptor partner, they considerably overlap in their use of downstream signaling components and enzymatic pathways, ultimately leading to the activation of the transcription factors NF-κB and IRF3/7. While NF-κB triggers transcriptional activation of pro-inflammatory cytokines and chemoattractant cytokines and chemokines, IRF3/7 induces type I (IFNβ) and III (IFNλ) interferons (IFNs). IFNs are then key autocrine and paracrine regulators of the antiviral state thanks to their ability to induce a plethora of interferon-stimulated genes (ISGs) that can inhibit viral replication while triggering cell growth arrest and apoptosis [34,35,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65].

The natural target cells of HPV are keratinocytes that form the stratified squamous epithelium of the skin and mucosal sites (e.g., the ano-genital or upper respiratory tract). Despite the fact that keratinocytes express several PRRs, which are able to sense viral pathogens and promote the innate immune response, HPVs have been very successful throughout evolution in creating an unreactive cellular milieu suitable for viral replication, persistence, and tumorigenesis [66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82].

The consensus model of cervical cancer progression clearly indicates as unifying risk factors the establishment of a persistent infection by hrHPV genotypes and the deregulation of normal viral gene expression, leading to steady-state E6/E7 overexpression. It is now widely accepted that HPV viral DNA integrates into the host genome quite frequently, especially during persistent HPV infection by hr genotypes. This event in turn stabilizes transcription of E6 and E7, thus conferring a growth advantage to the host cells. Despite the fact that approximately 90% of all HPV infections are resolved by the host immune system within a 2-year period, some patients may develop persistent HPV infections for years and eventually develop cancer, thus indicating that the innate immune reaction of the infected cells has been impaired in these cases. Even though the molecular determinants of this deficient immune response are potentially druggable targets to restore the innate immune response in HPV-transformed cells, they are still poorly characterized [2,3,6,8,15,16,17,76,83,84].

A major obstacle to understanding the true impact of E6/E7 on the host immune response is the difficulty in putting together pieces of data obtained using different experimental model and cell lines, which can easily create bias, especially when dealing with innate immunity. Indeed, current experimental models to study HPV-associated tumors are notoriously flawed by a number of limitations, mostly because HPV can only replicate and complete its life cycle in stratified squamous epithelial sites, which are quite difficult to model in vivo. Moreover, HPV can complete its viral life cycle in vitro only when keratinocytes are grown in organotypic raft culture, but, even in this case, the efficiency of viral replication is usually quite low. To further complicate matters, no animal model of infection is currently available for hr human genotypes (e.g., HPV16 and HPV18). Thus, the study of the cross talk between HPV and host cells has been mostly carried out in keratinocytes grown as monolayers. This cell system unfortunately has a series of caveats affecting the interpretation and generalizability of the findings, with the heterogeneity of the model of HPV infection being at the top of the list. In short, currently available cell models of HPV infection/transformation are based on the following strategies: (i) infection with HPV16 pseudovirions or virions; (ii) lentiviral-mediated overexpression of E6 and E7 from HPV16 or HPV18 by; (iii) transfection with episomal viral genomes; and (iv) transformed cells harboring multiple copies of the integrated or episomal viral genome.

With regard to HPV-associated disease models, it is particularly crucial to distinguish between models of infection where the viral genome is replicating in the infected cells and those where the pathogenic impact of the virus is solely due to deregulated E6/E7 expression. This latter model appears to fully recapitulate the status of HPV-transformed cells given that the viral genome is no longer replicating and, in most cases, is integrated as a partial genome. This condition can also be artificially obtained when cells are stably transduced with retroviral vectors expressing E6 and E7 or in proliferating cells stably maintaining episomal viral genomes after several passages in culture. The interface or interplay of the virus with the host innate immune system under these two different physical statuses of the virus, also characterized by a distinct pattern of viral protein expression, has not been fully elucidated yet. In addition, while a number of excellent reviews have already addressed the events occurring during the early phases of HPV infection, describing the cross talk between the host cell innate immune system and viral replication, there is lack of reviews focusing on the molecular mechanisms underlying the E6/E7-mediated dampening of the innate immune response in HPV-transformed keratinocytes, where these oncoproteins are aberrantly regulated [72,73,74,75,76,85]. Thus, here we take a close look at recent advances showing how viral immune escape mechanisms may contribute to the development and maintenance of a transformed phenotype during HPV-driven carcinogenesis. Since HPV16 and HPV18 account for almost 70% of all HPV-associated cancers, our analysis will be predominantly focused on the literature dealing with these two genotypes [1,16,17,18,86].