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Updated: May 6, 2026

A Primary Neuron Culture System for the Study of Herpes Simplex Virus Latency and Reactivation
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A Structural Atlas of TAP Inhibition by Herpesviruses and Poxviruses

James Lee1,2,3, Victor Manon1,2,4,3, Jue Chen1,2

  • 1Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065.

Biorxiv : the Preprint Server for Biology
|July 4, 2025
PubMed

Insights

Viruses like herpesviruses and poxviruses use proteins to block the transporter associated with antigen processing (TAP), hiding infected cells from immune detection. Structural studies reveal these viral TAP inhibitors share a common strategy to evade immune surveillance.

Area of Science:

  • Structural biology
  • Immunology
  • Virology

Background:

  • Host-pathogen interactions involve viral evasion of immune responses.
  • Herpesviruses and poxviruses encode proteins to inhibit the transporter associated with antigen processing (TAP).
  • TAP is crucial for MHC-I antigen presentation, presenting viral peptides to cytotoxic T cells.

Purpose of the Study:

  • To determine the structures of viral TAP inhibitors bound to TAP.
  • To create a structural atlas of viral strategies for TAP evasion.
  • To understand the mechanism of immune evasion by viral TAP inhibitors.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to resolve structures.
  • Structures were determined for TAP in complex with four viral inhibitors: BNLF2a, hUS6, bUL49.5, and CPXV012.
  • Comparative structural analysis was performed.

Main Results:

  • The structures of four viral TAP inhibitors (BNLF2a, hUS6, bUL49.5, CPXV012) complexed with TAP were determined.
  • These inhibitors, despite divergent sequences and folds, share a common mechanism of action.
  • They stall TAP's alternating access cycle, preventing peptide entry into the endoplasmic reticulum.

Conclusions:

  • Viral TAP inhibitors converge on a common strategy to block TAP function.
  • This blockade prevents cytotoxic T-cell recognition of infected cells, facilitating lifelong infections.
  • The structural framework provides insights for designing novel antiviral therapies.

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