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

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          Abstract

          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.

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          Herpes simplex virus turns off the TAP to evade host immunity.

          Many viruses have evolved mechanisms to avoid detection by the host immune system. Herpes simplex virus (HSV) expresses an immediate early protein, ICP47, which blocks presentation of viral peptides to MHC class I-restricted cells. The properties of the newly synthesized class I molecules in HSV-infected cells resemble those of cell lines deficient in the transporter associated with antigen processing (TAP) in that class I molecules are retained in the endoplasmic reticulum, and the heavy chain and beta 2-microglobulin subunits dissociate in detergent extracts but the complex can be stabilized by peptides. We show here that ICP47 binds to TAP and prevents peptide translocation into the endoplasmic reticulum.
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            Induction of MHC class I genes in neurons.

            Whether neurons express major histocompatibility complex (MHC) class I genes has not been firmly established. The techniques of confocal laser microscopy, patch clamp electrophysiology, and reverse transcriptase-polymerase chain reaction were combined here to directly examine the inducibility of MHC class I genes in individual cultured rat hippocampal neurons. Transcription of MHC class I genes was very rare in neurons with spontaneous action potentials. In electrically silent neurons, transcription was noted, with expression of beta 2-microglobulin under tighter control than in class I heavy chain molecules. Surface expression of class I molecules occurred only in electrically silent neurons treated with interferon gamma. Immunosurveillance by cytotoxic T cells may be focused on functionally impaired neurons.
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              A viral inhibitor of peptide transporters for antigen presentation.

              Cytotoxic T lymphocytes lyse target cells after T-cell-receptor-mediated recognition of class I major histocompatibility complex molecules presenting peptides. Antigenic peptides are generated in the cytoplasm by proteasomes and translocated into the lumen of the endoplasmic reticulum (ER) by peptide transporters (TAP). Herpes simplex virus (HSV) expresses a cytoplasmic protein, ICP47, which seems to interfere with such immune surveillance by mediating retention of 'empty' class I molecules in the ER. By expressing ICP47 in HeLa cells under an inducible promoter, we show that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides. This inhibition was overcome by transfecting murine TAP. Further, we demonstrate that ICP47 colocalizes and physically associates with TAP within the cell. Inhibition of peptide translocation by a viral protein indicates a previously undocumented potential mechanism for viral immune evasion.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                2 February 1998
                : 187
                : 3
                : 341-348
                Affiliations
                From the [* ]Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201, and the []Department of Ophthalmology and Visual Sciences, and the Department of Pathology, University of Illinois at Chicago, Chicago, Illinois 60612
                Author notes

                Address correspondence to Robert L. Hendricks at his current address, Department of Ophthalmology, Rm. 920, Eye and Ear Institute, University of Pittsburgh Medical Center, 203 Lothrop St., Pittsburgh, PA 15213. Phone: 412-647-5754; Fax: 412-647-5880; E-mail: bobhend@ 123456vision.eei.upmc.edu

                Article
                10.1084/jem.187.3.341
                2212130
                9449714
                c7b2636d-be86-441e-b6ab-2de9f227fd97
                Copyright @ 1998
                History
                : 14 August 1997
                : 6 November 1997
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                Medicine
                Medicine

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