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Journal of Virology, June 2005, p. 7024-7041, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7024-7041.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

5'-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

K.-S. Kim,1 S. Tracy,1 W. Tapprich,2 J. Bailey,2,{dagger} C.-K. Lee,1,{ddagger} K. Kim,1 W. H. Barry,3 and N. M. Chapman1*

Enterovirus Research Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198,1 Department of Biology, University of Nebraska, Omaha, Nebraska 68182-0040,2 Division of Cardiology, University of Utah Health Science Center, Salt Lake City, Utah 841323

Received 22 October 2004/ Accepted 25 January 2005

Adult human enteroviral heart disease is often associated with the detection of enteroviral RNA in cardiac muscle tissue in the absence of infectious virus. Passage of coxsackievirus B3 (CVB3) in adult murine cardiomyocytes produced CVB3 that was noncytolytic in HeLa cells. Detectable but noncytopathic CVB3 was also isolated from hearts of mice inoculated with CVB3. Sequence analysis revealed five classes of CVB3 genomes with 5' termini containing 7, 12, 17, 30, and 49 nucleotide deletions. Structural changes (assayed by chemical modification) in cloned, terminally deleted 5'-nontranslated regions were confined to the cloverleaf domain and localized within the region of the deletion, leaving key functional elements of the RNA intact. Transfection of CVB3 cDNA clones with the 5'-terminal deletions into HeLa cells generated noncytolytic virus (CVB3/TD) which was neutralized by anti-CVB3 serum. Encapsidated negative-strand viral RNA was detected using CsCl-purified CVB3/TD virions, although no negative-strand virion RNA was detected in similarly treated parental CVB3 virions. The viral protein VPg was detected on CVB3/TD virion RNA molecules which terminate in 5' CG or 5' AG. Detection of viral RNA in mouse hearts from 1 week to over 5 months postinoculation with CVB3/TD demonstrated that CVB3/TD virus strains replicate and persist in vivo. These studies describe a naturally occurring genomic alteration to an enteroviral genome associated with long-term viral persistence.

* Corresponding author. Mailing address: Department of Pathology and Microbiology, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495. Phone: (402) 559-7735. Fax: (402) 559-4077. E-mail: nchapman{at}unmc.edu.

{dagger} Present address: University of Nebraska Medical Center, Omaha NE 68198.

{ddagger} Present address: Department of Laboratory Medicine, Korea University Guro Hospital, Guro-gu, Guro-dong 80, Seoul, Korea 152-050.

Journal of Virology, June 2005, p. 7024-7041, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.7024-7041.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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