Poliovirus (PV), when injected intramuscularly into the calf, is incorporated into the sciatic nerve and causes an initial paralysis of the inoculated limb in transgenic mice carrying the human PV receptor (hPVR/CD155) gene. Here, we demonstrated by using an immunoelectron microscope that PV particles exist on vesicle structures in nerve terminals of neuromuscular junctions. We also demonstrated in glutathione S-transferase pulldown experiments that the dynein light chain, Tctex-1, interacts directly with the cytoplasmic domain of hPVR. In the axons of differentiated rat PC12 cells transfected with expression vectors for hPVRs, vesicles composed of PV and hPVR␣, as well as a mutant hPVR␣ (hPVRM␣) that had a reduced ability to bind Tctex-1, colocalized with Tctex-1. However, vesicles containing PV, dextran, and hPVR␣ had only retrograde motion, while those containing PV, dextran, and hPVRM␣ had anterograde or retrograde motion. Topical application of the antimicrotubule agent vinblastine to the sciatic nerve reduced the amount of virus transported from the calf to the spinal cord. These results suggest that direct efficient interaction between the cytoplasmic domain and Tctex-1 is essential for the efficient retrograde transport of PV-containing vesicles along microtubules in vivo.In humans, paralytic poliomyelitis is considered to result from an invasion by circulating poliovirus (PV) into the central nervous system, probably via the blood-brain barrier. The notion is supported by a previous study using a mouse model (44). In that study, it was demonstrated that circulating PV after intravenous inoculation appears to cross the blood-brain barrier at a high rate, and the neural dissemination pathway from the skeletal muscle is not the primary dissemination route of the circulating virus to the central nervous system. Along with this pathway of dissemination, a neural pathway has been reported in humans (32), monkeys (20), and PV-sensitive transgenic (Tg) mice carrying the human PV receptor (hPVR/ CD155) gene (35,36), and it appears to be important in causing provocation poliomyelitis (14). Using the Tg mouse line, we demonstrate that PV inoculated into the calf is incorporated into the sciatic nerve and retrogradely transported through the axons as intact virion particles, that one of the fast retrograde axonal transport systems is involved in viral dissemination, and that the pathogenesis of PV infection via the neural pathway is inhibited by the anti-hPVR monoclonal antibody (MAb) p286, which is able to block the infection (35).hPVR is a member of the immunoglobulin (Ig) superfamily, with three linked extracellular Ig-like domains followed by a membrane-spanning domain and a cytoplasmic domain (CP). Two membrane-bound forms (hPVR␣ and hPVR␦) and two secreted forms (hPVR and hPVR␥) derived by alternative splicing are potentially expressed in human cells (28). Membrane-bound hPVRs are considered to play important roles in the early steps of infection, such as binding of the virus to the cell surface, penetration...