Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection

JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are generally asymptomatic, but immune-compromised and immune-suppressed patients are at risk for the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Studies with purified JCPyV found it undergoes receptor-dependent infectious entry requiring both lactoseries tetrasaccharide C (LSTc) attachment and 5-hydroxytryptamine type 2 entry receptors. Subsequent work discovered the major targets of JCPyV infection in the central nervous system (oligodendrocytes and astrocytes) do not express the required attachment receptor at detectable levels, virus could not bind these cells in tissue sections, and viral quasi-species harboring recurrent mutations in the binding pocket for attachment. While several research groups found evidence JCPyV can use novel receptors for infection, it was also discovered that extracellular vesicles (EVs) can mediate receptor independent JCPyV infection. Recent work also found JCPyV associated EVs include both exosomes and secretory autophagosomes. EVs effectively present a means of immune evasion and increased tissue tropism that complicates viral studies and anti-viral therapeutics. This review focuses on JCPyV infection mechanisms and EV associated and outlines key areas of study necessary to understand the interplay between virus and extracellular vesicles.