Measles virus spread between neurons requires cell contact but not CD46 expression, syncytium formation, or extracellular virus production

In patients with subacute sclerosing panencephalitis (SSPE), which is assoc iated,vith persistent measles virus (MV) infection in the brain, little inf ectious virus can be recovered despite the presence of viral RNA and protei n. Based on studies of brain tissue from SSPE patients and our work with MV -infected NSE-CD46(+) mice, which express the measles receptor CD46 on neur ons, several lines of evidence suggest that the mechanism of viral spread i n the central nervous system differs from that in nonneuronal cells. To exa mine this alternate mechanism of viral spread, as well as the basis for the loss of normal transmission mechanisms, infection and spread of MV Edmonst on was evaluated in primary CD46(+) neurons from transgenic mice and differ entiated human NT2 neurons. As expected, unlike that between fibroblasts, v iral spread between neurons occurred in the absence of syncytium formation and with minimal extracellular virus. Electron microscopy analysis showed t hat viral budding did not occur from the neuronal surface, although nucleoc apsids were present in the cytoplasm and aligned at the cell membrane. We o bserved many examples of nucleocapsids present in the neuronal processes an d aligned at presynaptic neuronal membranes. Cocultures of CD46(+) and CD46 (-)neurons showed that cell contact but not CD46 expression is required for MV spread between neurons. Collectively, these results suggest that the ne uronal environment prevents the normal mechanisms of MV spread between neur ons at the level of viral assembly but allows an alternate, CD46-independen t mechanism of viral transmission, possibly through the synapse.