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Journal of Virology, June 2002, p. 6172-6184, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6172-6184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Neuroblastoma Cell-Adapted Yellow Fever 17D Virus: Characterization of a Viral Variant Associated with Persistent Infection and Decreased Virus Spread

Leonsia A. Vlaycheva and Thomas J. Chambers*

Department of Molecular Microbiology and Immunology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104

Received 25 October 2001/ Accepted 11 March 2002

Serial passage of yellow fever 17D virus (YF5.2iv, derived from an infectious molecular clone) on mouse neuroblastoma (NB41A3) cells established a persistent noncytopathic infection associated with a variant virus. This virus (NB15a) was dramatically reduced in plaque formation and exhibited impaired replication kinetics on all cell lines examined compared to the parental virus. Nucleotide sequence analysis of NB15a revealed a substitution in domain III of the envelope (E) protein at residue 360, where an aspartic acid residue was replaced by glycine. Single mutations were also found within the NS2A and NS3 proteins. Engineering of YF5.2iv virus to contain the E360 substitution yielded a virus (G360 mutant) whose plaque size and growth efficiency in cell culture resembled those of NB15a. Compared with YF5.2iv, both NB15a and G360 were markedly restricted for spread through Vero cell monolayers and mildly restricted in C6/36 cells. On NB41A3 cells, spread of the viruses was similar, but all three were generally inefficient compared with spread in other cell lines. Compared to YF5.2iv virus, NB15a was uniformly impaired in its ability to penetrate different cell lines, but a difference in cell surface binding was detected only on NB41A3 cells, where NB15a appeared less efficient. Despite its small plaque size, impaired growth, and decreased penetration efficiency, NB15a did not differ from YF5.2iv in mouse neurovirulence testing, based on mortality rates and average survival times after intracerebral inoculation of young adult mice. The data indicate that persistence of yellow fever virus in NB41A3 cells is associated with a mutation in the receptor binding domain of the E protein that impairs the virus entry process in cell culture. However, the phenotypic changes which occur in the virus as a result of the persistent infection in vitro do not correlate with attenuation during pathogenesis in the mouse central nervous system.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, St. Louis University Health Sciences Center, 1402 South Grand Ave., St. Louis, MO 63104. Phone: (314) 577-8447. Fax: (314) 773-3403. E-mail: chambetj{at}slu.edu.

Journal of Virology, June 2002, p. 6172-6184, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6172-6184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nickells, J., Cannella, M., Droll, D. A., Liang, Y., Wold, W. S. M., Chambers, T. J. (2008). Neuroadapted Yellow Fever Virus Strain 17D: a Charged Locus in Domain III of the E Protein Governs Heparin Binding Activity and Neuroinvasiveness in the SCID Mouse Model. J. Virol. 82: 12510-12519 [Abstract] [Full Text]  
  • Vlaycheva, L., Nickells, M., Droll, D. A., Chambers, T. J. (2005). Neuroblastoma cell-adapted yellow fever virus: mutagenesis of the E protein locus involved in persistent infection and its effects on virus penetration and spread. J. Gen. Virol. 86: 413-421 [Abstract] [Full Text]  
  • Kumar, A. S. M., Reddi, H. V., Kung, A. Y., Dal Canto, M., Lipton, H. L. (2004). Virus Persistence in an Animal Model of Multiple Sclerosis Requires Virion Attachment to Sialic Acid Coreceptors. J. Virol. 78: 8860-8867 [Abstract] [Full Text]  
  • Nickells, M., Chambers, T. J. (2003). Neuroadapted Yellow Fever Virus 17D: Determinants in the Envelope Protein Govern Neuroinvasiveness for SCID Mice. J. Virol. 77: 12232-12242 [Abstract] [Full Text]  


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