The isogenic host attachment spike protein recombinant demyelinating strain of mouse hepatitis virus (MHV) (RSA59) and the nondemyelinating strain (RSMHV2) differ in their abilities to infect distinct types of neural cells, spread from cell to cell, and induce subsequent demyelination and axonal loss. The differential demyelination properties of RSA59 and RSMHV2 may be a function of spike protein-mediated neuronal transport. Disruption of microtubules with colchicine and vinblastine significantly blocks neuronal transport and reduces the replication of RSA59, whereas RSMHV2 remains unaffected.