Borna disease virus persistent infection activates mitogen-activated protein kinase and blocks neuronal differentiation of PC12 cells

Persistence of Borna disease virus (BDV) in the central nervous system caus es damage to specific neuronal populations. BDV is noncytopathic, and the m echanisms underlying neuronal pathology are not well understood. One hypoth esis is that infection affects the response of neurons to factors that are crucial for their proliferation, differentiation, or survival. To test this hypothesis, we analyzed the response of PC12 cells persistently infected w ith BDV to the neurotrophin nerve growth factor (NGF). PC12 is a neural cre st-derived cell line that exhibits features of neuronal differentiation in response to NGF. We report that persistence of BDV led to a progressive cha nge of phenotype of PC12 cells and blocked neurite outgrowth in response to NGF. Infection downregulated the expression of synaptophysin and growth-as sociated protein-43, two molecules involved in neuronal plasticity, as well as the expression of the chromaffin-specific gene tyrosine hydroxylase. We showed that the block in response to NGF was due in part to the down-regul ation of NGF receptors. Moreover, although BDV caused constitutive activati on of the ERK1/2 pathway, activated ERKs were not translocated to the nucle us efficiently. These observations may account for the absence of neuronal differentiation of persistently infected PC12 cells treated with NGF.