Infected Cell Protein (ICP)47 Enhances Herpes Simplex Virus Neurovirulence by Blocking the CD8⁺ T Cell Response

The herpes simplex virus (HSV) infected cell protein (ICP)47 blocks CD8⁺ T cell recognition of infected cells by inhibiting the transporter associated with antigen presentation (TAP). In vivo, HSV-1 replicates in two distinct tissues: in epithelial mucosa or epidermis, where the virus enters sensory neurons; and in the peripheral and central nervous system, where acute and subsequently latent infections occur. Here, we show that an HSV-1 ICP47⁻ mutant is less neurovirulent than wild-type HSV-1 in mice, but replicates normally in epithelial tissues. The reduced neurovirulence of the ICP47⁻ mutant was due to a protective CD8⁺ T cell response. When compared with wild-type virus, the ICP47⁻ mutant expressed reduced neurovirulence in immunologically normal mice, and T cell–deficient nude mice after reconstitution with CD8⁺ T cells. However, the ICP47⁻ mutant exhibited normal neurovirulence in mice that were acutely depleted of CD8⁺ T cells, and in nude mice that were not reconstituted, or were reconstituted with CD4⁺ T cells. In contrast, CD8⁺ T cell depletion did not increase the neurovirulence of an unrelated, attenuated HSV-1 glycoprotein (g)E⁻ mutant. ICP47 is the first viral protein shown to influence neurovirulence by inhibiting CD8⁺ T cell protection.