Evasion of host immune defenses by human papillomavirus

Abstract

A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses.

Keywords: APOBEC3; Adaptive immunity; DNA methylation; HPV; Histone modification; Immune evasion; Innate immunity; Oncogene; Papillomavirus; Restriction factor; Tumor virus; Virus evolution.

Fig. 1

HPV alters transcription of key immune modulators. (A) Gene transcription of IFN-κ and CXCL14 is repressed by high-risk HPV E6 and E7, respectively, through DNA methylation. HPV16 E7 interacts with DNMT1 and enhances its activity, but the ability of E6 to influence host DNA methylation is unknown. High-risk HPV E7 represses transcription of TLR9 and/or IRF1 responsive genes by (B) inducing K27 methylation and (C) reducing K4 methylation and acetylation of histone molecules. (D) NF-κB signaling is inhibited by high-risk HPV E6 and E7 through inhibiting K310 acetylation of p65. me, 5-methylcytidine; Me, methyl lysine; Ac, acetyl lysine; E2BS, E2 binding site.

Fig. 2

HPV E6 and E7 interacts with core components of the interferon pathway. (A) HPV inhibits type I IFN receptor signaling by HPV E6 and E7 interactions with TYK2 and IRF9, respectively. (B) HPV inhibits signaling by the DNA sensor cGAS via high-risk HPV E6 and E7 interactions with IRF3 and STING, respectively. (C) HPV inhibits type II IFN receptor signaling by high-risk E7 interaction with IRF1. (D) The HPV oncoproteins E6 and/or E7 suppress IRF3 activation by inhibiting K63 ubiquitination of TRAF3 through downregulation of UCHL1. (E) Interaction between high-risk HPV E6 and E6AP facilitates poly-ubiquitination and degradation of pro-IL-1β. P, phosphorylation; GAS, gamma interferon activation site; Ub, ubiquitination.

Fig. 3

HPV E5 and E7 downregulate surface expression of MHC molecules. HPV E5 binds to MHC-I, CD1d, and the invariant chain of MHC-II in the Golgi and ER, preventing their trafficking to the cell surface. High-risk HPV E7 represses transcription of MHC-I genes.

Fig. 4

Bias in dinucleotide frequencies suggest that host restriction may drive papillomavirus genome evolution. (A) Unmethylated papillomavirus genomes can be recognized by TLR9 and/or targeted for methylation-induced gene silencing. During coevolution with their hosts, papillomaviruses have been selected and enriched for variants that contain reduced CpG motifs. CpG dinucleotide depletion may reflect an important immune evasion strategy. (B) Mucosal skin expresses high levels of nearly all A3 isoforms, including the HPV restriction factor A3A. The Alphapapillomaviruses are a genus of papillomaviruses that preferentially infect mucosal skin. TpC depletion amongst the Alphapapillomaviruses may allow for evasion of A3A at mucosal sites. DNMT, DNA methyltransferases.