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Journal of Virology, May 2009, p. 4912-4922, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02343-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Neurodegeneration Induced by PVC-211 Murine Leukemia Virus Is Associated with Increased Levels of Vascular Endothelial Growth Factor and Macrophage Inflammatory Protein 1 and Is Inhibited by Blocking Activation of Microglia

Xiujie Li, Charlotte Hanson, Joan L. Cmarik, and Sandra Ruscetti^*

Laboratory of Cancer Prevention, National Cancer Institute—Frederick, Frederick, Maryland 21702

Received 10 November 2008/ Accepted 28 February 2009

PVC-211 murine leukemia virus (MuLV) is a neuropathogenic retrovirus that has undergone genetic changes from its nonneuropathogenic parent, Friend MuLV, that allow it to efficiently infect rat brain capillary endothelial cells (BCEC). To clarify the mechanism by which PVC-211 MuLV expression in BCEC induces neurological disease, we examined virus-infected rats at various times during neurological disease progression for vascular and inflammatory changes. As early as 2 weeks after virus infection and before any marked appearance of spongiform neurodegeneration, we detected vessel leakage and an increase in size and number of vessels in the areas of the brain that eventually become diseased. Consistent with these findings, the amount of vascular endothelial growth factor (VEGF) increased in the brain as early as 1 to 2 weeks postinfection. Also detected at this early disease stage was an increased level of macrophage inflammatory protein 1 (MIP-1), a cytokine involved in recruitment of microglia to the brain. This was followed at 3 weeks postinfection by a marked accumulation of activated microglia in the spongiform areas of the brain accompanied by an increase in tissue plasminogen activator, a product of microglia implicated in neurodegeneration. Pathological observations at the end stage of the disease included loss of neurons, decreased myelination, and mild muscle atrophy. Treatment of PVC-211 MuLV-infected rats with clodronate-containing liposomes, which specifically kill microglia, significantly blocked neurodegeneration. Together, these results suggest that PVC-211 MuLV infection of BCEC results in the production of VEGF and MIP-1, leading to the vascular changes and microglial activation necessary to cause neurodegeneration.

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* Corresponding author. Mailing address: Laboratory of Cancer Prevention, Building 567, Room 152, National Cancer Institute—Frederick, Frederick, MD 21702-1201. Phone: (301) 846-5740. Fax: (301) 846-6164. E-mail: ruscetti{at}ncifcrf.gov

Published ahead of print on 11 March 2009.

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Journal of Virology, May 2009, p. 4912-4922, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02343-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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