The Role of Chemokines during Viral Infection of the CNS

Hosking, Martin P.; Lane, Thomas E.

A potential consequence of chemokine secretion and the subsequent accumulation of leukocytes within the CNS, while important for viral control in many instances, is the development of neuropathology. For example, the fatal meningoencephalitis induced by LCMV infection is mediated by infiltration of virusspecific CTLs that promote subsequent myeloid cell and leukocyte entry [15, 25] . During infection with LCMV (Traub), genetic silencing of CXCL10 or its receptor CXCR3 reduces the infiltration of CD8+ T cells, conferring either partial or near complete protection from immunopathology and death [26, 27] . However, CXCL10 remains dispensable for T cell infiltration or the development of fatal inflammation during infection with LCMV (Armstrong) [28] , further highlighting underlying differences in viral strains and chemokine utilization with regards to disease outcome. During JHMV infection, sustained CXCL10 and CCL5 expression leads to continuing immune cell infiltration that manifests an immune-mediated demyelinating disease. Neutralization of either chemokine during persistent JHMV infection abrogates the immune infiltration and greatly reduces both disease severity and demyelination [29, 30] . In addition to attracting inflammatory cells that contribute to neuropathology, CXCL10, which is chronically expressed within the brains of patients suffering from HIV-associated neurological disorders, can directly induce neuronal cell death [5] . In addition, proteolytically cleaved CXCL12, which is also detectable within the brains of HIV-1infected patients, is capable of inducing neurotoxicity and apoptosis [31] . Although beyond the scope of this review, extensive work has focused upon the direct and indirect roles of the chemokine receptors CXCR4 and CCR5 (and their associated ligands) in contributing to HIV-associated dementia (reviewed in [32, 33] ). Therefore, chemokines are critical mediators of neuropathology during viral infections of the CNS, either by attracting pathogenic inflammatory cells or directly mediating neurotoxicity and cell death.