The UL41 gene product (vhs) of herpes simplex virus (HSV) is packaged in the virion, and mediates host protein synthesis shutoff at the early stage of the virus replication cycle, In order to clarify the role of vhs in virus replication and virulence, we isolated a completely UL41-deficient mutant (the VR Delta 41 strain) and its revertant (the VR Delta 41R strain), In the mouse encephalitis model, the replication of strain VR Delta 41 was inhibited after 2 days post-infection, resulting in low virulence, by gamma-ray-sensitive cells such as lymphocytes and/or neutrophils, The result suggested that some cytokines, produced in VR Delta 41-inoculated brains, activate and induce the migration of gamma-ray-sensitive cells to the infection site. Therefore, cytokines produced by HSV-l-infected human cells were screened, and potent inductions of interleukin (IL)-1 beta, IL-8 and macrophage inflammatory protein-1 alpha by VR Delta 41 infection were observed, Moreover, the VR Delta 41 strain showed 20- and 5-fold higher sensitivity to interferon-alpha and -beta compared to the wild-type strain, respectively. These results indicate that one important role of vhs in vivo is evasion from non-specific host defence mechanisms during primary infection through suppression of cytokine production in HSV-infected cells and reduction of the anti-HSV activity of interferon-alpha and -beta.