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Journal of Virology, April 2007, p. 3563-3573, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02494-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Heparan Sulfate Binding Can Contribute to the Neurovirulence of Neuroadapted and Nonneuroadapted Sindbis Viruses{triangledown}

Kate D. Ryman,1* Christina L. Gardner,1 Crystal W. Burke,1 Kathryn C. Meier,1 Joseph M. Thompson,2 and William B. Klimstra1

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932,1 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72902

Received 13 November 2006/ Accepted 3 January 2007

Cell culture-adapted laboratory strains of Sindbis virus (SB) exhibit efficient initial attachment to cell surface heparan sulfate (HS) receptors. In contrast, non-cell-adapted strains, such as the SB consensus sequence virus TR339, interact weakly with HS and cell surfaces. Regardless of their HS binding phenotype, most SB strains do not cause fatal disease in adult mice, whether inoculated subcutaneously (s.c.) or intracranially (i.c.). However, laboratory strains of SB can be rendered neurovirulent for adult mice by introduction of a glutamine (Gln)-to-histidine (His) mutation at position 55 of the E2 envelope glycoprotein. In the current work, we have determined that E2 His 55-containing viruses require a second-site mutation (Glu to Lys) at E2 position 70 that confers efficient HS binding in order to exhibit virulence for adult mice and that virulence is correlated with very high infectivity for many cell types. Furthermore, introduction of E2 Lys 70 or certain other HS-binding mutations alone also increased morbidity and/or mortality over that of TR339 for older mice inoculated i.c. However, all viruses containing single HS-binding mutations were attenuated in s.c. inoculated suckling mice in comparison with TR339. These results suggest that HS binding may attenuate viral disease that is dependent on high-titer viremia; however, efficient cell attachment through HS binding can increase virulence, presumably through enhancing the replication of SB within specific host tissues such as the brain.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932. Phone: (318) 675-6684. Fax: (318) 675-5764. E-mail: kryman{at}lsuhsc.edu.

{triangledown} Published ahead of print on 10 January 2007.

Journal of Virology, April 2007, p. 3563-3573, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02494-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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