JC Virus Enters Human Glial Cells by Clathrin-Dependent Receptor-Mediated Endocytosis

Abstract

The human polyomavirus JC virus (JCV) is the etiologic agent of a fatal central nervous system (CNS) demyelinating disease known as progressive multifocal leukoencephalopathy (PML). PML occurs predominantly in immunosuppressed patients and has increased dramatically as a result of the AIDS pandemic. The major target cell of JCV infection and lytic replication in the CNS is the oligodendrocyte. The mechanisms by which JCV initiates and establishes infection of these glial cells are not understood. The initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal ␣(2-6)-linked sialic acids. The subsequent steps of entry and targeting of the viral genome to the nucleus have not been described. In this report, we compare the kinetics and mechanisms of infectious entry of JCV into human glial cells with that of the related polyomavirus, simian virus 40 (SV40). We demonstrate that JCV, unlike SV40, enters glial cells by receptor-mediated clathrin-dependent endocytosis.JC virus (JCV) is a small, nonenveloped, double-stranded DNA containing virus belonging to the family Papovaviridae and the subfamily Polyomavirinae (23, 26). In vivo, JCV infection is restricted to oligodendrocytes, astrocytes, and B lymphocytes (17,20). This highly restricted cell type specificity is also seen in vitro, as JCV infects primary cultures of human glial cells, human glial cell lines, and to a limited extent, primary human B cells and some B-cell lines (4,17,20,28). The life cycle of JCV begins with virus attachment to a cell surface glycoprotein receptor containing ␣-(2-6)-linked sialic acid (15). Following attachment, the JCV virion must penetrate the plasma membrane and target its genome to the nucleus. Very little is known about the mechanisms of polyomavirus entry and nuclear targeting. Early work with the mouse polyomavirus and simian virus 40 (SV40) demonstrated that these virions were internalized into monopinocytotic vesicles which then accumulated at the nuclear membrane (12, 16). In some studies, viral particles were also seen in the nucleus, suggesting that the nucleus was the site of uncoating (7,19,21). More recent studies have shown that SV40 enters cells by receptor-mediated endocytosis into uncoated membrane-bound invaginations known as caveolae (1,2,24). An interaction between SV40 and major histocompatibility complex-encoded class I proteins induces the clustering of virus-receptor complexes into caveolin-rich membrane domains (5,8,24). Intracellular signals induced by SV40 binding to cells result in increased caveola-dependent endocytosis of the virus and delivery of the virions to the endoplasmic reticulum (9, 24). It is unclear how the viral genome is then targeted from the endoplasmic reticulum to the nucleus.In this report, we studied the kinetics of JCV and SV40 infectious entry into human glial cells. Our results demonstrate that JCV rapidly enters glial cells and is completely internalized into a neutralizing antibody-resistant compartment within 30 min. SV40 ...

Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature

“…30,[35][36][37] However, we did not appreciate any evidence of clinical improvement despite ziprasidone-inducing significant sedative side effects. These findings raise the question whether higher doses, than clinically tolerated, are required to achieve a beneficial effect.…”

“…or intrathecally), cidofovir i.v., alone or in combination, and withdrawal of immunosuppression medications. Pho et al 35 showed that the neuroleptic drug, chlorpromazine, inhibits the endocytic pathway used by JC virus to infect glial cells. Atwood.…”

BK Polyoma Virus Allograft Nephropathy: Ultrastructural Features from Viral Cell Entry to Lysis

“…The morphological findings are remarkably similar to SV40 and murine polyoma virus host cell entry. This is in contrast to the manner of entry of JC virus, that has been found to enter cells by following the usual endocytic pathway using clathrin-coated vesicles (20). The different pathways of viral cell entry do not appear to directly correlate with the type of receptor, since BK, JC and murine polyoma viruses have sialic-acid type receptors, whereas SV40 has receptors related to the MHC system (30).…”

“…Specific functional and molecular studies on the biological behavior of BK virus at the cellular level are not available, and very little is known about the interactions between the virus and the host cells. In contrast, numerous studies have characterized the cellular interactions of the SV40 virus and murine polyoma virus (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For the purpose of further understanding the pathogenicity of BK virus, it may be helpful to draw potential analogies with these better known polyoma viruses, particularly the SV40.…”

“…While there have been no studies specifically addressing these aspects of the BK virus infection, a well-conducted study has shown that JC virions use for cell entry the typical endocytic pathway with clathrincoated vesicles (20).…”