JC Polyomavirus Utilizes Clathrin-mediated Endocytosis for Infectious Entry

JC polyomavirus (JCPyV) establishes a lifelong, persistent, asymptomatic primary infection in the kidney in the majority of the human population. In immunocompromised individuals JCPyV disseminates to secondary sites of infection including the central nervous system where it establishes a lytic infection and is the causative agent of progressive multifocal leukoencephalopathy (PML), a fatal, demyelinating disease. JCPyV attachment is mediated by the interaction of viral capsid protein 1 (VP1) with α2,6-linked sialic acid LSTc. Following attachment, internalization is facilitated by 5–hydroxytryptamine (5-HT)2 receptors and is thought to occur through clathrin-mediated endocytosis (CME), yet the cellular factors required for internalization have not been characterized due to non-selective inhibitors and lack of an animal model. CME by 5-HT2 receptors is mediated by interactions of specific scaffolding proteins with clathrin including but not limited to β–arrestin, dynamin, and AP2. Treatment of cells with specific small molecule inhibitors, RNA interference, and dominant negative mutants resulted in diminished JCPyV infection. We have demonstrated that JCPyV entry of target cells is mediated by clathrin-dependent endocytosis requiring specific host cell proteins including clathrin, β–arrestin, AP2, and the molecular GTPase dynamin. Interestingly, inhibition of specific CME proteins required for JCPyV internalization did not impact entry of the closely related polyomavirus SV40 indicating that activation of CME for infectious entry is a JCPyV mediated event. These data demonstrate a deeper understanding of the cellular uptake mechanism utilized by JCPyV and gives insight into virus-mediated internalization strategies.

Faculty Mentor: Melissa Maginnis

Co-authors: Conner Lajoie, Jeanne DuShane