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 ...
Purpose: Despite the recent advances made in the treatment of multiple myeloma, the disease still remains incurable. The oncolytic potential of reovirus has previously been shown and is currently in phase III clinical trials for solid tumors. We tested the hypothesis that reovirus can successfully target human multiple myeloma in vitro, ex vivo, and in vivo without affecting human hematopoietic stem cell (HHSC) repopulation/differentiation in a murine model that partially recapitulates human multiple myeloma.Experimental Design: Human myeloma cell lines and ex vivo tumor specimens were exposed to reovirus and oncolysis and mechanisms of cell death were assessed. RPMI 8226GFPþ cells were injected intravenously to non-obese diabetic/severe combined immune deficient (NOD/SCID) mice and treated with live reovirus (LV) or dead virus (DV). Multiple myeloma disease progression was evaluated via whole-body fluorescence and bone marrow infiltration. HHSCs exposed to LV/DV were injected to NOD/SCID mice and repopulation/differentiation was monitored.Results: A total of six of seven myeloma cell lines and five of seven patient tumor specimens exposed to reovirus showed significant in vitro sensitivity. Tumor response of multiple myeloma by LV, but not DV, was confirmed by comparison of total tumor weights (P ¼ 0.05), and bone marrow infiltration (1/6, LV; 5/6, DV). Mice injected with LV-or DV-exposed HHSCs maintained in vivo re-population/lineage differentiation showing a lack of viral effect on the stem cell compartment. Reovirus oncolysis was mediated primarily by activation of the apoptotic pathways.Conclusions: The unique ability of reovirus to selectively kill multiple myeloma while sparing HHSCs places it as a promising systemic multiple myeloma therapeutic for clinical testing.
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