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Journal of Virology, May 2003, p. 5305-5312, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5305-5312.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Caspase Cleavage of the Nonstructural Protein NS1 Mediates Replication of Aleutian Mink Disease Parvovirus

Sonja M. Best, Janie F. Shelton, Justine M. Pompey, James B. Wolfinbarger, and Marshall E. Bloom*

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana 59840

Received 14 November 2002/ Accepted 11 February 2003

Virus-induced apoptosis of infected cells can limit both the time and the cellular machinery available for virus replication. Hence, many viruses have evolved strategies to specifically inhibit apoptosis. However, Aleutian mink disease parvovirus (ADV) is the first example of a DNA virus that not only induces apoptosis but also utilizes caspase activity to facilitate virus replication. To determine the function of caspase activity during ADV replication, virus-infected cell lysates or purified ADV proteins were incubated with various purified caspases. Caspases cleaved the major nonstructural protein of ADV (NS1) at two caspase recognition sequences, whereas ADV structural proteins could not be cleaved. Importantly, the NS1 products could be identified in ADV-infected cells but were not present in infected cells pretreated with caspase inhibitors. By mutating putative caspase cleavage sites (D to E), we mapped the two cleavage sites to amino acid residues NS1:227 (INTD{downarrow}S) and NS1:285 (DQTD{downarrow}S). Replication of ADV containing either of these mutations was reduced 103- to 104-fold compared to that of wild-type virus, and a construct containing both mutations was replication defective. Immunofluorescent studies revealed that cleavage was required for nuclear localization of NS1. The requirement for caspase activity during permissive replication suggests that limitation of caspase activation and apoptosis in vivo may be a novel approach to restricting virus replication.

* Corresponding author. Mailing address: Rocky Mountain Laboratories, 903 S. Fourth St., Hamilton, MT 59840. Phone: (406) 363-9275. Fax: (406) 363-9286. E-mail: mbloom{at}niaid.nih.gov.

Journal of Virology, May 2003, p. 5305-5312, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5305-5312.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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