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TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6

Yiqi Zhao1,2, Yongxu Lu1,2, Samuel Richardson3

  • 1Department of Pathology, University of Cambridge, Cambridge, UK.

Nature
|August 9, 2023
PubMed

Insights

Human TRIM5α (tripartite motif protein 5α) restricts orthopoxviruses by binding their capsid protein L3. Viral proteins C6 and cyclophilin A counteract this, but drugs like CsA inhibit them, offering antiviral potential.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Human tripartite motif protein 5α (TRIM5α) is known to restrict certain RNA viruses like HIV.
  • Its role in restricting DNA viruses, particularly orthopoxviruses, is less understood.

Purpose of the Study:

  • To investigate the antiviral activity of TRIM5α against orthopoxviruses.
  • To identify viral countermeasures and potential therapeutic targets.

Main Methods:

  • Demonstrated TRIM5α restriction of orthopoxviruses through SPRY domain binding to the L3 capsid protein.
  • Identified viral protein C6 and cyclophilin A (CypA) as counteracting factors.
  • Assessed the antiviral effects of cyclosporine A (CsA) and its derivatives (alisporivir, NIM811) in vitro.

Main Results:

  • TRIM5α restricts orthopoxviruses by binding the L3 capsid protein, inhibiting replication and activating innate immunity.
  • Orthopoxviruses employ C6 to degrade TRIM5α and CypA to antagonize TRIM5α via L3 interaction.
  • CsA, alisporivir, and NIM811 inhibit CypA, demonstrating antiviral activity against orthopoxviruses dependent on TRIM5α.

Conclusions:

  • TRIM5α acts as a restriction factor against orthopoxviruses.
  • Viral countermeasures involve TRIM5α degradation and antagonism by CypA.
  • CsA derivatives show promise as antiviral therapies against orthopoxviruses due to targeting the host factor CypA, limiting resistance emergence.

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