Retrovirus infection of the central nervous system can result in severe and debilitating neurological disease. An important example of this is Human Immunodeficiency Virus (HIV)-induced dementia, which affects approximately 10-20% of HIV-infected individuals. In HIV-dementia and in the animal models of SIV encephalitis, FIV encephalitis and polytropic murine retrovirus-induced neurological disease, the development of severe clinical disease is not associated with a remarkable amount of pathological damage in the CNS. Thus, the mechanism by which these retroviruses induce neurological disease is unclear. Increased expression of several host genes, including the proinflammatory cytokine TNF alpha and chemokines MCP-1, MIP-1 alpha, MIP-1 beta, and RANTES, have been shown to correlate with neurological symptoms in HIV-infected patients as well as in the animal models of SIV, FIV and polytropic murine retrovirus infection. However, it is unknown whether the increased expression of these genes is beneficial or detrimental to the host. The overall aim of this proposal is to study the role of proinflammatory cytokines and chemokines in retrovirus-induced neurological disease. Using the murine model of polytropic retrovirus-induced disease, we have shown that knockout mice deficient in the genes for either TNF alpha or CCR2,the primary receptor for MCP-1, are less susceptible to retrovirus-induced neurological disease than wild type controls. However, neither TNF alpha or CCR2 deficient mice were completely resistant to the neurovirulent polytropic retrovirus, Fr98. In the current proposal, we will determine if TNF alpha and MCP-1/CCR2 are the primary mediators of neurological disease by analyzing double knockout mice deficient in both TNFalpha and CCR2 for susceptibility to Fr98-induced neurological disease. Additionally, we will determine if over expression of TNF alpha and/or MCP-1 in the CNS can induce clinical symptoms during infection with an avirulent polytropic retrovirus, Fr54. Finally, using in situ hybridization we determined that TNF alpha and MCP-1 are not produced by infected microglia cells, but rather uninfected cell types including neurons and astrocytes. Therefore, we will also analyze how infected microglia cells regulate TNF alpha and MCP-1production, in vivo.
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