20980500
not annotated - annotated - LINNAEUS only
Differential regulation of human papillomavirus type 8 by interferon regulatory factors 3 and 7.
The genus Beta human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus Beta HPV infections are limited. Interferon regulatory factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5' phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients.
Ann file
T1 Species 27 54 human papillomavirus type 8
N1 Reference T1 Taxonomy:337051
T2 Species 109 147 Beta human papillomavirus (HPV) type 8
N2 Reference T2 Taxonomy:337051
T3 Species 356 370 genus Beta HPV
N3 Reference T3 Taxonomy:337051
T4 Species 709 714 human
N4 Reference T4 Taxonomy:9606
T5 Species 736 740 HPV8
N5 Reference T5 Taxonomy:337051
T6 Species 834 838 HPV8
N6 Reference T6 Taxonomy:337051
T7 Species 936 941 human
N7 Reference T7 Taxonomy:9606
T8 Species 968 972 HPV8
N8 Reference T8 Taxonomy:337051
T9 Species 1067 1071 HPV8
N9 Reference T9 Taxonomy:337051
T10 Species 1138 1143 HPV16
N10 Reference T10 Taxonomy:337041
T11 Species 1149 1153 HPV8
N11 Reference T11 Taxonomy:337051
T12 Species 1488 1493 human
N12 Reference T12 Taxonomy:9606
T13 Species 1647 1651 HPV8
N13 Reference T13 Taxonomy:337051