Learning deficits in mice with persistent Borna disease virus infection of the CNS associated with elevated chemokine expression.

Borna disease virus (BDV) is a highly neurotropic RNA virus that causes a CD8(+) T cell-mediated neurological disease in certain mouse strains. We established asymptomatic persistent central nervous system (CNS) infections in mutant C57BL/10J mice that lack functional CD8(+) T cells. When analyzed at adult age for spatial learning abilities in a water maze, BDV-infected mice showed slightly impaired escape performance while their exploratory behavior in an openfield test was indistinguishable from uninfected control mice. Histological and molecular biological analysis revealed extensive viral spread throughout the CNS of infected animals. Most neurons of the hippocampus contained viral antigen, but there was no overt loss of neurons from this structure. We found almost unchanged levels of the proinflammatory cytokines IL-1beta and TNF-alpha, but clearly increased levels of the chemokines IP-10 and RANTES in brains of infected mice. Re-examination of water maze data revealed that only infected mice with IP-10 transcript levels above a certain threshold showed impaired performance, whereas the performance of infected mice with lower IP-10 levels was indistinguishable from uninfected controls. This suggests that BDV infection can disturb the function of the mammalian CNS without causing overt neuronal loss, and that the magnitude of virus-induced chemokine production in the CNS correlates with the degree of impairment.