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Journal of Virology, November 2004, p. 12480-12488, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12480-12488.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Transition from Acute to Persistent Theiler's Virus Infection Requires Active Viral Replication That Drives Proinflammatory Cytokine Expression and Chronic Demyelinating Disease{dagger}

Mark Trottier,1,2,{ddagger} Brian P. Schlitt,1 Aisha Y. Kung,1 and Howard L. Lipton1,2,3,4*

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

Received 30 April 2004/ Accepted 25 June 2004

The dynamics of Theiler's murine encephalomyelitis virus (TMEV) RNA replication in the central nervous systems of susceptible and resistant strains of mice were examined by quantitative real-time reverse transcription-PCR and were found to correlate with host immune responses. During the acute phase of infection in both susceptible and resistant mice, levels of viral replication were high in the brain and brain stem, while levels of viral genome equivalents were 10- to 100-fold lower in the spinal cord. In the brain, viral RNA replication decreased after a peak at 5 days postinfection (p.i.), in parallel with the appearance of virus-specific antibody responses; however, by 15 days p.i., viral RNA levels began to increase in the spinal cords of susceptible mice. During the transition to and the persistent phase of infection, the numbers of viral genome equivalents in the spinal cord varied substantially for individual mice, but high levels were consistently associated with high levels of proinflammatory Th1 cytokine and chemokine mRNAs. Moreover, a large number of viral genome equivalents and high proinflammatory cytokine mRNA levels in spinal cords were only observed for susceptible SJL/J mice who developed demyelinating disease. These results suggest that TMEV persistence requires active viral replication beginning about day 11 p.i. and that active viral replication with high viral genome loads leads to increased levels of Th1 cytokines that drive disease progression in infected mice.

* Corresponding author. Mailing address: Evanston Northwestern Healthcare Research Institute, 2650 Ridge Ave., Evanston, IL 60201. Phone: (847) 570-2168. Fax: (847) 570-1568. E-mail: hllipton{at}northwestern.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org.

{ddagger} Present address: Biology Department, New York University, New York, NY 10003.

Journal of Virology, November 2004, p. 12480-12488, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12480-12488.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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