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Journal of Virology, April 2006, p. 4114-4121, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.4114-4121.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Apoptosis of Liver-Derived Cells Induced by Parvovirus B19 Nonstructural Protein

Brian D. Poole,^1,2, Jing Zhou,² Amy Grote,² Adam Schiffenbauer,² and Stanley J. Naides^1,2,3*

Huck Institutes for Life Sciences, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033,¹ Division of Rheumatology, Department of Medicine, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033,² Departments of Microbiology and Immunology and of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania 17033³

Received 7 October 2005/ Accepted 11 January 2006

Parvovirus B19 has been implicated in some cases of acute fulminant non-A, non-B, non-C, non-G liver failure. Our laboratory previously demonstrated that B19 infection of hepatocytes induces apoptosis and that the B19 viral nonstructural protein, NS1, may play a critical role. To study the involvement of NS1 in apoptosis of liver cells, we generated a fusion protein of NS1 with enhanced green fluorescent protein (eGFP) in a system allowing for inducible gene expression. Transfection of the liver-derived cell line HepG2 with the eGFP/NS1 vector allowed expression of the fusion protein, which was visualized by fluorescence microscopy and demonstrated by immunoblotting. The fusion protein localized to discrete domains in the nucleus. Transfection of HepG2 cells with the eGFP/NS1 vector led to apoptosis of 35% of transfected cells, a sevenfold increase over cells transfected with the parent eGFP expression vector. Mutation of the eGFP/NS1 vector to eliminate the nucleoside triphosphate-binding site of NS1 significantly decreased apoptosis, as did treatment of transfected cells with inhibitors of caspase 3 or 9. Neutralization of tumor necrosis factor alpha or Fas ligand had no effect on apoptosis. These results demonstrate that NS1 is sufficient to induce apoptosis in liver-derived cells and that it does so through the initiation of an intrinsic caspase pathway.

Present address: Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Okla.

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