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.
Goldsmith
K
K
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Chen
W
W
Johnson
D C
DC
Hendricks
R L
RL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003315:Cornea / Q000821:virology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016296:Mutagenesis / Q000235:genetics; D017933:Peripheral Nervous System / Q000821:virology; D017384:Sequence Deletion / Q000235:genetics; D018139:Simplexvirus / Q000472:pathogenicity*; D012867:Skin / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology; D014774:Virulence
C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D014764:Viral Proteins