Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

Author summary Persistent infection with high-risk human papillomavirus may lead to a variety of cancers in human including cervical cancer, anal cancer, head and neck cancer and skin cancer. There has been a lack of animal model to study how papillomavirus infection evades cellular immune surveillance to establish long-term infections to cause cancers. We utilized a mouse papillomavirus, MmuPV1, as an infection model in immunocompetent FVB/N mice to study how the virus escapes immune recognition to establish persistent infections. We found a novel regulator, stress keratin 17 (K17), was induced in expression following MmuPV1 infection, and that K17 was critical for preventing T cell infiltration in MmuPV1-induced papillomas by inhibiting the CXCL9/CXCL10/CXCR3 axis. Our study provides a new mechanism by which papillomaviruses evade T cell response following infection. High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. We used a mouse papillomavirus infection model to characterize virus-host interactions. We found that mouse papillomavirus (MmuPV1) suppresses host immune responses via overexpression of stress keratins. In mice deficient for stress keratin K17 (K17KO), we observed rapid regression of papillomas dependent on T cells. Cellular genes involved in immune response were differentially expressed in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8(+) T cells and upregulation of IFN gamma-related genes, including CXCL9 and CXCL10, prior to complete regression. Blocking the receptor for CXCL9/CXCL10 prevented early regression. Our data provide a novel mechanism by which papillomavirus-infected cells evade host immunity and defines new therapeutic targets for treating persistent papillomavirus infections.