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Journal of Virology, March 2001, p. 2848-2856, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2848-2856.2001

Differences in Cytokine and Chemokine Responses during Neurological Disease Induced by Polytropic Murine Retroviruses Map to Separate Regions of the Viral Envelope Gene

Karin E. Peterson,1 Shelly J. Robertson,2 John L. Portis,1 and Bruce Chesebro1,*

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,1 and Department of Molecular Biology, University of Wyoming---Laramie, Laramie, Wyoming 820712

Received 25 August 2000/Accepted 20 December 2000

Infection of the central nervous system (CNS) by several viruses can lead to upregulation of proinflammatory cytokines and chemokines. In immunocompetent adults, these molecules induce prominent inflammatory infiltrates. However, with immunosuppressive retroviruses, such as human immunodeficiency virus (HIV), little CNS inflammation is observed yet proinflammatory cytokines and chemokines are still upregulated in some patients and may mediate pathogenesis. The present study examined expression of cytokines and chemokines in brain tissue of neonatal mice infected with virulent (Fr98) and avirulent (Fr54) polytropic murine retroviruses. While both viruses infect microglia and endothelia primarily in the white matter areas of the CNS, only Fr98 induces clinical CNS disease. The pathology consists of gliosis with minimal morphological changes and no inflammation, similar to HIV. In the present experiments, mice infected with Fr98 had increased cerebellar mRNA levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha ), TNF-beta , and interleukin-1alpha and chemokines macrophage inflammatory protein-1alpha (MIP-1alpha ), MIP-1beta , monocyte chemoattractant protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), and RANTES compared to mice infected with Fr54 or mock-infected controls. The increased expression of these genes occurred prior to the development of clinical symptoms, suggesting that these cytokines and chemokines might be involved in induction of neuropathogenesis. Two separate regions of the Fr98 envelope gene are associated with neurovirulence. CNS disease associated with the N-terminal portion of the Fr98 env gene was preceded by upregulation of cytokines and chemokines. In contrast, disease associated with the central region of the Fr98 env gene showed no upregulation of cytokines or chemokines and thus did not require increased expression of these genes for disease induction.

* Corresponding author. Mailing address: Rocky Mountain Laboratories, 903 S. 4th St., Hamilton, MT 59840. Phone: (406) 363-9354. Fax: (406) 363-9286. E-mail: bchesebro{at}nih.gov.

Journal of Virology, March 2001, p. 2848-2856, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2848-2856.2001


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