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Primary cultures of human oligodendrocytes (HOLs) were established from six different donors. Differences in resistance to infection with herpes simplex virus 1 (HSV-1) were determined between the primary cultures of HOL in tissue culture infective dose 50 (TCID(50)), indirect immunofluoresence (IF), and serial electron microscopy (EM) studies. Virus production at different multiplicities of infection (MOIs) indicated that differences in HSV-1 replication were statistically significant and MOI-dependent. Overall, virus yield from the HOL cultures infected at an MOI of 1 increased up to 6 days postinfection (PI); no additional enhancement occurred at 7 days PI. However, differences in the replication capacity of the six HOL cultures observed at 5 days PI persisted at 6 and 7 days PI. When taken together, the results of these investigations indicate that, similar to experimental animals, resistance to HSV-1 differs between primary cultures of HOL and is donor-dependent. The results also raise the possibility that similar to experimental animals, resistance to HSV-1, mediated at the level of HOL, may be genetically determined. Furthermore, permissive infections of primary cultures of HOL were established with HSV-1 over a wide range of MOIs, similar to results obtained with viral infection of primary murine oligodendrocytes, but neither latent nor abortive infections of HOL were induced in vitro, even at very low MOIs. Resistance to HSV-1, mediated by glial cells, is a nonimmune mechanism that may influence the development of acute CNS infection in man as well as individual susceptibility to this virus., (Copyright 2002 Wiley-Liss, Inc.)