Human Beta Papillomavirus Type 8 E1 and E2 Proteins Suppress the Activation of the RIG-I-Like Receptor MDA5

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 RIG-I, MDA5, TLR3, and STING to analyze a potential functional interaction. We found that primary skin keratinocytes and U2OS cells expressed RIG-I, MDA5, TLR3, and STING, but not TLR7, TLR8, or TLR9. While HPV16-E6 downregulated the expression of RIG-I, MDA5, TLR3, and STING and, in conjunction with HPV16-E7, 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-E2, which was associated with an elevated expression of TLR3. Nevertheless, whole HPV8 genome expression, as well as the selective expression of HPV8-E1 or HPV8-E2, was found to suppress MDA5-induced type I IFN and the proinflammatory cytokine IL-6. Furthermore, RNA isolated from HPV8-E2 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-E2 in keratinocytes leads to the formation of stimulatory RNA ligands that require the active suppression of immune recognition. These results identify HPV8-E1 and HPV8-E2 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.

Keywords: human papillomavirus type 8 (HPV8); immune system; innate immunity; nucleic acid detection; pattern recognition receptors; receptor signaling; virus host interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Betapapillomavirus* / genetics
  • Humans
  • Interferon-Induced Helicase, IFIH1 / metabolism*
  • Keratinocytes
  • Leukocytes, Mononuclear / metabolism
  • Nucleic Acids* / metabolism
  • Oncogene Proteins, Viral* / genetics
  • Papillomavirus Infections* / metabolism
  • RNA / metabolism
  • Toll-Like Receptor 3 / metabolism
  • Viral Envelope Proteins / metabolism*


  • Nucleic Acids
  • Oncogene Proteins, Viral
  • Toll-Like Receptor 3
  • Viral Envelope Proteins
  • RNA
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1

Grants and funding

S.R. was supported by German Cancer Aid (Deutsche Krebshilfe, grant 70112729) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG), grant AK 42/10-1). C.C. and C.H. were supported by German Cancer Aid (Deutsche Krebshilfe, grant 70112729) and M.H. and B.A. were supported by German Cancer Aid (Deutsche Krebshilfe, grant 70112727). G.H. was supported by Germany’s Excellence Strategy–EXC2151–390873048 (ID 369799452–TRR237 and ID 397484323–TRR259), and by the German Center for Infectious Diseases (Deutsches Zentrum für Infektionsforschung (DZIF), TTU 07.834_00).