Human papillomavirus type 16 E5 inhibits interferon signaling and supports episomal viral maintenance.
Human papillomaviruses (HPVs) infect keratinocytes of stratified epithelia. Long-term persistence of infection is a critical risk factor for the development of HPV-induced malignancies. Through the action of its oncogenes, HPV evades host immune responses to facilitate its productive life cycle. In this work, we have discovered a previously unknown function of the HPV16 E5 oncoprotein in the suppression of interferon responses. This suppression is focused on keratinocyte-specific IFNκ and is mediated through E5-induced changes in growth factor signaling pathways as identified through phosphoproteomics analysis. The loss of E5 in keratinocytes maintaining the complete HPV16 genome results in the de-repression of IFNK transcription and subsequent JAK/STAT-dependent upregulation of several ISGs at both mRNA and protein levels. We also establish a link between the loss of E5 and the subsequent loss of genome maintenance and stability, resulting in increased genome integration.Importance Persistent human papillomavirus infections can cause a variety of significant cancers. The ability of HPV to persist depends on evasion of the host immune system. In this study, we show that the HPV16 E5 protein can suppress an important aspect of the host immune response. In addition, we find that the E5 protein is important for helping the virus avoid integration into the host genome, which is a frequent step along the pathway to cancer development.