Live long and persist: polyomavirus immune evasion in the brain and kidney

Polyomaviruses (PyVs) are widespread commensals among vertebrates, including humans, where they silently persist lifelong in healthy hosts. Polyomavirus infection in immunocompromised individuals can cause life-threatening diseases. Of the 14 human polyomaviruses discovered to date, resurgent infections by the JC and BK PyVs are responsible for high morbidity and mortality in individuals with certain inherited or acquired immune perturbations. JCPyV causes several brain disorders, the most fully characterized and of highest (albeit rare) incidence being Progressive Multifocal Leukoencephalopathy (PML). BKPyV infection elicits a diffuse interstitial nephritis in up to 10% of allograft kidneys, and approximately 10% of allogeneic hematopoietic stem cell transplant recipients develop BKPyV-associated hemorrhagic cystitis. No clinically efficacious anti-PyV agents are available. Because PyVs are species-specific, determinants of pathogenesis by human PyVs are inferred from infection of cells in tissue culture. Insights into viral and immunological factors that enable PyVs to persist and cause central nervous system (CNS) and kidney disease in vivo have emerged from recent studies using mouse PyV (MuPyV), a natural murine pathogen. In this perspective, we discuss recent findings using the MuPyV-mouse model to understand early immunovirologic events of CNS and kidney infection, the development of PyV antiviral agents, and promising research directions for polyomavirology.