INFECTED CELL PROTEIN (ICP)47 ENHANCES HERPES-SIMPLEX VIRUS NEUROVIRULENCE BY BLOCKING THE CD8(-CELL RESPONSE() T)

The herpes simplex virus (HSV) infected cell protein (ICP)47 blocks CD 8(+) T cell recognition of infected cells by inhibiting the transporte r associated with antigen presentation (TAP). In vivo, HSV-1 replicate s in two distinct tissues: in epithelial mucosa or epidermis, where th e virus enters sensory neurons; and in the peripheral and central nerv ous system, where acute and subsequently latent infections occur. Here , we show that an HSV-1 ICP47(-) mutant is less neurovirulent than wil d-type HSV-1 in mice, but replicates normally in epithelial tissues. T he reduced neurovirulence of the ICP17(-) mutant was due to a protecti ve CD8(+) T cell response. When compared with wild-type virus, the ICP 47(-) mutant expressed reduced neurovirulence in immunologically norma l mice, and T cell-deficient nude mice after reconstitution with CD8() T cells. However, the ICP47(-) mutant exhibited normal neurovirulenc e in mice that were acutely depleted of CD8(+) T cells, and in nude mi ce that were not reconstituted, or were reconstituted with CD4(+) T ce lls. In contrast, CD8(+) T cell depletion did not increase the neurovi rulence of an unrelated, attenuated HSV-1 glycoprotein (g)E- mutant. I CP47 is the first viral protein shown to influence neurovirulence by i nhibiting CD8(+) T cell protection.