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Journal of Virology, December 2004, p. 13104-13112, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13104-13112.2004

Separate Sequences in a Murine Retroviral Envelope Protein Mediate Neuropathogenesis by Complementary Mechanisms with Differing Requirements for Tumor Necrosis Factor Alpha

Karin E. Peterson,^* Scott Hughes, Derek E. Dimcheff, Kathy Wehrly, and Bruce Chesebro

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana

Received 14 May 2004/ Accepted 15 July 2004

The innate immune response, through the induction of proinflammatory cytokines and antiviral factors, plays an important role in protecting the host from pathogens. Several components of the innate response, including tumor necrosis factor alpha (TNF-), monocyte chemoattractant protein 1, interferon-inducible protein 10, and RANTES, are upregulated in the brain following neurovirulent retrovirus infection in humans and in animal models. However, it remains unclear whether this immune response is protective, pathogenic, or both. In the present study, by using TNF-^–/– mice we analyzed the contribution of TNF- to neurological disease induced by four neurovirulent murine retroviruses, with three of these viruses encoding portions of the same neurovirulent envelope protein. Surprisingly, only one retrovirus (EC) required TNF- for disease induction, and this virus induced less TNF- expression in the brain than did the other retroviruses. Analysis of glial fibrillary acidic protein and F4/80 in EC-infected TNF-^–/– mice showed normal activation of astrocytes but not of microglia. Thus, TNF--mediated microglial activation may be important in the pathogenic process initiated by EC infection. In contrast, TNF- was not required for pathogenesis of the closely related BE virus and the BE virus induced disease in TNF-^–/– mice by a different mechanism that did not require microglial activation. These results provide new insights into the multifactorial mechanisms involved in retrovirus-induced neurodegeneration and may also have analogies to other types of neurodegeneration.

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* Corresponding author. Present address: Department of Pathobiological Sciences, School of Veterinary Medicine, Skip Bertman Dr., Louisiana State University, Baton Rouge, LA 70803. Phone: (225) 578-9681. Fax: (225) 578-9701. E-mail: kpeterson{at}vetmed.lsu.edu.

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Journal of Virology, December 2004, p. 13104-13112, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13104-13112.2004

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