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8.A.72 The Immune Evasion Protein, ICP47 (ICP47) Family 

IPC47 of the CDD Herpres_US12 Family plays a role in the inhibition of host immune responses. It binds specifically within the channels of transporters associated with antigen processing (TAP; see below), thereby blocking peptide-binding and translocation by TAP as well as subsequent loading of peptides onto MHC class I molecules.

Cellular immunity against viral infection and tumour cells depends on antigen presentation by major histocompatibility complex class I (MHC I) molecules. Intracellular antigenic peptides are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I molecules, which are exported to the cell surface and present peptides to the immune system (York et al. 1994). Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumour development. To escape immune surveillance, some viruses have evolved strategies to either downregulate TAP expression or directly inhibit TAP activity. Oldham et al. 2016 described the cryo-electron microscopy structure of human TAP in complex with ICP47, a small protein produced by the herpes simplex virus I. The 12 transmembrane helices and 2 cytosolic nucleotide-binding domains of the transporter adopt an inward-facing conformation with the two nucleotide-binding domains separated. The viral inhibitor ICP47 forms a long helical hairpin, which plugs the translocation pathway of TAP from the cytoplasmic side. Association of ICP47 precludes substrate binding and prevents nucleotide-binding domain closure necessary for ATP hydrolysis. This work illustrates immune evasion by persistent viruses. By blocking viral antigens from entering the endoplasmic reticulum, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host.

References associated with 8.A.72 family:

Oldham, M.L., N. Grigorieff, and J. Chen. (2016). Structure of the transporter associated with antigen processing trapped by herpes simplex virus. Elife 5:. 27935481
Oldham, M.L., R.K. Hite, A.M. Steffen, E. Damko, Z. Li, T. Walz, and J. Chen. (2016). A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter. Nature 529: 537-540. 26789246
York, I.A., C. Roop, D.W. Andrews, S.R. Riddell, F.L. Graham, and D.C. Johnson. (1994). A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell 77: 525-535. 8187174