Human Papillomavirus E7 oncoprotein increases production of the anti-inflammatory IL-18 binding protein (IL-18BP) in keratinocytes

Human papillomavirus can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of IL-18 binding protein (IL-18BP). This anti-inflammatory protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared amongst E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7 expressing keratinocytes are capable of diminishing IL-18 mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor. Importance: Infection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL-18BP production is a reduction in CD4 positive lymphocyte activation in response to IL-18 co-stimulation. These findings may shed light on the immune evasion abilities of HPV.