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Journal of Virology, August 2004, p. 8909-8916, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8909-8916.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Heparan Sulfate-Independent Infection Attenuates High-Neurovirulence GDVII Virus-Induced Encephalitis

Honey V. Reddi,1,2 A. S. Manoj Kumar,1,2 Aisha Y. Kung,1 Patricia D. Kallio,1 Brian P. Schlitt,1 and Howard L. Lipton1,3,4*

Department of Neurology, Evanston Hospital,1 Departments of Neurology,3 Microbiology-Immunology,4 Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois2

Received 13 January 2004/ Accepted 30 March 2004

The high-neurovirulence Theiler's murine encephalomyelitis virus (TMEV) strain GDVII uses heparan sulfate (HS) as a coreceptor to enter target cells. We report here that GDVII virus adapted to growth in HS-deficient cells exhibited two amino acid substitutions (R3126L and N1051S) in the capsid and no longer used HS as a coreceptor. Infectious-virus yields in CHO cells were 25-fold higher for the adapted virus than for the parental GDVII virus, and the neurovirulence of the adapted virus in intracerebrally inoculated mice was substantially attenuated. The adapted virus showed altered cell tropism in the central nervous systems of mice, shifting from cerebral and brainstem neurons to spinal cord anterior horn cells; thus, severe poliomyelitis, but not acute encephalitis, was observed in infected mice. These data indicate that the use of HS as a coreceptor by GDVII virus facilitates cell entry and plays an important role in cell tropism and neurovirulence in vivo.

* Corresponding author. Mailing address: Department of Neurology, Evanston Hospital, 2650 Ridge Ave., Evanston, IL 60201. Phone: (847) 570-2168. Fax: (847) 570-1568. E-mail: hllipton{at}northwestern.edu.

Journal of Virology, August 2004, p. 8909-8916, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8909-8916.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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