INFECTION OF GLIAL-CELLS BY THE HUMAN POLYOMAVIRUS JC IS MEDIATED BY AN N-LINKED GLYCOPROTEIN CONTAINING TERMINAL ALPHA(2-6)-LINKED SIALIC ACIDS

The human JC polyomavirus (JCV) is the etiologic agent of the fatal ce ntral nervous system (CNS) demyelinating disease progressive multifoca l leukoencephalopathy (PML). PML typically occurs in immunosuppressed patients and is the direct result of JCV infection of oligodendrocytes , The initial event in infection of cells by JCV is attachment of the virus to receptors present on the surface of a susceptible cell. Our l aboratory has been studying this critical event in the life cycle of J CV, and we have found that JCV binds to a limited number of cell surfa ce receptors on human glial cells that are not shared by the related p olyomavirus simian virus 40 (C. K. Liu, A. P. Hope, and W. J. Atwood, J. Neurovirol. 4:49-58, 1998). To further characterize specific JCV re ceptors on human glial cells, we tested specific neuraminidases, prote ases, and phospholipases for the ability to inhibit JCV binding to and infection of glial cells. Several of the enzymes tested were capable of inhibiting virus binding to cells, but only neuraminidase was capab le of inhibiting infection. The ability of neuraminidase to inhibit in fection correlated with its ability to remove both alpha(2-3)- and alp ha(2-6)-linked sialic acids from glial cells. A recombinant neuraminid ase that specifically removes the a(2-3) linkage of sialic acid had no effect on virus binding or infection. A competition assay between vir us and sialic acid-specific lectins that recognize either the alpha(2- 3) or the a(2-6) linkage revealed that JCV preferentially interacts wi th a(2-6)linked sialic acids on glial cells. Treatment of glial cells with tunicamycin, but not with benzyl N-acetyl-alpha-D-galactosaminide , inhibited infection by JCV, indicating that the sialylated JCV recep tor is an N-linked glycoprotein. As sialic acid containing glycoprotei ns play a fundamental role in mediating many virus-cell and cell-cell recognition processes, it will be of interest to determine what role t hese receptors play in the pathogenesis of PML.