Human papillomavirus E7 oncoprotein increases production of the anti-inflammatory interleukin-18 binding protein in keratinocytes

• Published in: Journal of virology 2014-04, Vol.88 (8), p.4173-4179
• Main Authors: Richards, Kathryn H, Doble, Rosella, Wasson, Christopher W, Haider, Mohammed, Blair, G Eric, Wittmann, Miriam, Macdonald, Andrew
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Human papillomavirus; Human papillomavirus 16 - chemistry; Human papillomavirus 16 - genetics; Human papillomavirus 16 - immunology; Human papillomavirus 18 - chemistry; Human papillomavirus 18 - genetics; Human papillomavirus 18 - immunology; Human papillomavirus 6 - chemistry; Human papillomavirus 6 - genetics; Human papillomavirus 6 - immunology; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Keratinocytes - immunology; Keratinocytes - virology; Papillomavirus E7 Proteins - chemistry; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - immunology; Papillomavirus Infections - genetics; Papillomavirus Infections - immunology; Papillomavirus Infections - virology; Up-Regulation; Virus-Cell Interactions
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.02546-13

Human papillomavirus (HPV) 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 interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding 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 among 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. 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 costimulation. These findings may shed light on the immune evasion abilities of HPV.