JC Polyomavirus Makes Facultative Use of Glycosaminoglycans For Infectious Entry Into Cells
Friday, September 18, 2015 — Poster Session V
* FARE Award Winner
- EM Geoghegan
- CB Buck
JC polyomavirus (JCV) commonly infects the urinary tract of healthy adults. Although the infection generally does not cause overt disease in immunocompetent individuals, in immunocompromised individuals JCV can cause the lethal brain disease progressive multifocal encephalopathy (PML). It is known that wild-type (wt) JCV utilizes sialylated glycans as receptors for infectious entry into cells. Surprisingly, the predominant JCV strains found in the brains of PML patients contain mutations that disrupt the sialic acid (SA) binding site. These mutants readily infect primary brain cells, however, suggesting the existence of a SA-independent entry pathway. Our findings document the existence of this alternative entry pathway and show that it requires a non-sialylated class of polysaccharides called glycosaminoglycans (GAGs). Both wt and PML-mutant JCVs fail to bind a CHO cell line that lacks GAGs, yet they both bind CHOs lacking SA. In an inhibition assay with exogenous heparin, the infectivity of the wt virus is inhibited by 50%, while the infectivity of PML-mutant virus is completely abolished. This suggests that the wt virus can use either the known SA-dependent pathway or the GAG-dependent pathway, while the mutant is restricted to the GAG pathway. Treatment of cells with a sialyltransferase inhibitor reduced the infectivity of wt JCV by about 50%, while the PML-mutant viruses are slightly enhanced, indicating the GAG-dependent pathway remains operational. This research defines a novel alternative entry pathway that mutant JCV strains use to enter cells, thus providing a target for treatment and prevention of PML.