Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany.
Institute of Virology, Medical Faculty and University Hospital Cologne, University of Cologne, Fürst-Pückler-Str. 56., 50935 Cologne, Germany.
Viruses. 2022 Jun 22;14(7):1361. doi: 10.3390/v14071361.
Persistent infections of the skin with the human papillomavirus of genus beta (β-HPV) in immunocompetent individuals are asymptomatic, but in immunosuppressed patients, β-HPV infections exhibit much higher viral loads on the skin and are associated with an increased risk of skin cancer. Unlike with HPV16, a high-risk α-HPV, the impact of β-HPV early genes on the innate immune sensing of viral nucleic acids has not been studied. Here, we used primary skin keratinocytes and U2OS cells expressing HPV8 or distinct HPV8 early genes and well-defined ligands of the nucleic-acid-sensing receptors , , , and to analyze a potential functional interaction. We found that primary skin keratinocytes and U2OS cells expressed , , , and , but not , , or . While HPV16- downregulated the expression of , , , and and, in conjunction with HPV16-, effectively suppressed type I IFN in response to MDA5 activation, the presence of HPV8 early genes showed little effect on the expression of these immune receptors, except for HPV8-, which was associated with an elevated expression of TLR3. Nevertheless, whole HPV8 genome expression, as well as the selective expression of HPV8- or HPV8-, was found to suppress MDA5-induced type I IFN and the proinflammatory cytokine IL-6. Furthermore, RNA isolated from HPV8- expressing primary human keratinocytes, but not control cells, stimulated a type I IFN response in peripheral blood mononuclear cells, indicating that the expression of HPV8- in keratinocytes leads to the formation of stimulatory RNA ligands that require the active suppression of immune recognition. These results identify HPV8- and HPV8- as viral proteins that are responsible for the immune escape of β-HPV from the innate recognition of viral nucleic acids, a mechanism that may be necessary for establishing persistent β-HPV infections.
在免疫功能正常的个体中，β-HPV（人乳头瘤病毒属β）持续感染皮肤是无症状的，但在免疫抑制患者中，β-HPV 感染的皮肤病毒载量更高，并且与皮肤癌风险增加相关。与高危型 α-HPV（人乳头瘤病毒 16 型）不同，β-HPV 早期基因对病毒核酸的先天免疫感应的影响尚未得到研究。在这里，我们使用表达 HPV8 或特定 HPV8 早期基因以及核酸感应受体的、和的原代皮肤角质形成细胞和 U2OS 细胞，分析了潜在的功能相互作用。我们发现原代皮肤角质形成细胞和 U2OS 细胞表达、和，但不表达、、或。虽然 HPV16-下调了、、和的表达，并且与 HPV16-一起，有效地抑制了 MDA5 激活后 I 型 IFN 的产生，但 HPV8 早期基因的存在对这些免疫受体的表达几乎没有影响，除了 HPV8-，它与 TLR3 的表达升高有关。然而，整个 HPV8 基因组的表达，以及 HPV8-或 HPV8-的选择性表达，被发现抑制了 MDA5 诱导的 I 型 IFN 和促炎细胞因子 IL-6 的产生。此外，从表达 HPV8-的原代人角质形成细胞中分离的 RNA，但不是对照细胞，刺激了外周血单核细胞中的 I 型 IFN 反应，表明角质形成细胞中 HPV8-的表达导致了刺激 RNA 配体的形成，这些配体需要积极抑制免疫识别。这些结果表明 HPV8-和 HPV8-是负责 β-HPV 逃避病毒核酸先天识别的病毒蛋白，这一机制可能是建立持续性 β-HPV 感染所必需的。
