No abstract

Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association studywas performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.HPV is a small non-enveloped double-stranded DNA virus that infects keratinocytes. Most HPV infections clear spontaneously, however, persistent HPV infection is strongly associated with risk of several cancers including cervical, laryngeal, esophageal and anal cancer 1 . In immunosuppressed individuals there is a higher rate of cervical and anal HPV infections 2 . HPV infection favors HIV acquisition, and HIV-infected individuals encompass a heavier burden of HPV-induced dysplasia and cancer due to progressive immune suppression and impaired cell-mediated immunity. Persistent HPV infections are strong determinants of anal high-grade squamous intraepithelial lesions (HSIL) 3 .Innate immune responses are characterized by production of a complex network of cytokines that effectively activate cellular immune cells 4 . Pattern recognition receptors (PRRs) include the RNA-binding helicase family of RIG-I-like receptors (RLR: RIG-I and MDA5), and the family of Toll-like receptors (TLR). In response to viral infections, produced type I interferons (IFN) activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, which, in turn, induces the expression of additional interferon signaling