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Journal of Virology, December 2006, p. 12060-12069, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01650-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CD4+ T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System{triangledown}

Elizabeth M. Sitati1 and Michael S. Diamond1,2,3*

Departments of Molecular Microbiology,1 Medicine,2 Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri 631103

Received 1 August 2006/ Accepted 25 September 2006

Although studies have established that innate and adaptive immune responses are important in controlling West Nile virus (WNV) infection, the function of CD4+ T lymphocytes in modulating viral pathogenesis is less well characterized. Using a mouse model, we examined the role of CD4+ T cells in coordinating protection against WNV infection. A genetic or acquired deficiency of CD4+ T cells resulted in a protracted WNV infection in the central nervous system (CNS) that culminated in uniform lethality by 50 days after infection. Mice surviving past day 10 had high-level persistent WNV infection in the CNS compared to wild-type mice, even 45 days following infection. The absence of CD4+ T-cell help did not affect the kinetics of WNV infection in the spleen and serum, suggesting a role for CD4-independent clearance mechanisms in peripheral tissues. WNV-specific immunoglobulin M (IgM) levels were similar to those of wild-type mice in CD4-deficient mice early during infection but dropped ~20-fold at day 15 postinfection, whereas IgG levels in CD4-deficient mice were ~100- to 1,000-fold lower than in wild-type mice throughout the course of infection. WNV-specific CD8+ T-cell activation and trafficking to the CNS were unaffected by the absence of CD4+ T cells at day 9 postinfection but were markedly compromised at day 15. Our experiments suggest that the dominant protective role of CD4+ T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8+ T-cell responses in the CNS that enable viral clearance.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu.

{triangledown} Published ahead of print on 11 October 2006.

Journal of Virology, December 2006, p. 12060-12069, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01650-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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