Learning deficits in mice with persistent Borna disease virus infection ofthe CNS associated with elevated chemokine expression

Borna disease virus (BDV) is a highly neurotropic RNA virus that causes a C D8(+) T cell-mediated neurological disease in certain mouse strains. We est ablished asymptomatic persistent central nervous system (CNS) infections in mutant C57BL/10J mice that lack functional CD8(+) T cells. When analyzed a t adult age for spatial learning abilities in a water maze, BDV-infected mi ce showed slightly impaired escape performance while their exploratory beha vior in an openfield test was indistinguishable from uninfected control mic e. Histological and molecular biological analysis revealed extensive viral spread throughout the CNS of infected animals. Most neurons of the hippocam pus contained viral antigen, but there was no overt loss of neurons from th is structure. We found almost unchanged levels of the proinflammatory cytok ines IL-1 beta and TNF-alpha, but clearly increased levels of the chemokine s 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. (C) 2001 Elsevier Science B.V. All rights reserved.