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Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response

Seungmin Hwang1, Kyeong Seon Kim, Emilio Flano

  • 1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Cell Host & Microbe
|February 17, 2009
PubMed

Insights

A herpesvirus protein, ORF36, blocks the immune system's interferon response. This immune evasion is crucial for viral infection and persistence, as demonstrated in murine gamma-herpesvirus 68 (MHV-68) studies.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Herpesviral kinases are essential for viral replication.
  • Murine gamma-herpesvirus 68 (MHV-68) possesses a conserved kinase, ORF36.
  • The specific functions of ORF36 in host immune interaction are not fully understood.

Purpose of the Study:

  • To investigate the role of MHV-68 ORF36 in the host's antiviral defense mechanisms.
  • To elucidate the molecular mechanisms by which ORF36 interacts with the host immune system.
  • To determine the importance of ORF36's anti-interferon activity for viral pathogenesis and persistence.

Main Methods:

  • Screening of mutant viruses lacking ORF36.
  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Analysis of viral replication and immune response in vitro and in vivo.

Main Results:

  • ORF36 was identified as an inhibitor of the type I interferon (IFN) response.
  • ORF36 directly binds to activated interferon regulatory factor 3 (IRF-3) in the nucleus.
  • This binding prevents IRF-3 from interacting with CBP, suppressing the interferon beta promoter.
  • MHV-68 lacking ORF36 showed increased IFN response and attenuated viral infection and latency.
  • The anti-IFN function is conserved across herpesvirus subfamilies, independent of kinase activity.

Conclusions:

  • Herpesviruses utilize the conserved kinase ORF36 to counteract the host's type I interferon response.
  • This anti-interferon activity is a critical mechanism for viral immune evasion and persistence.
  • Targeting ORF36's anti-IFN function could be a strategy to control herpesvirus infections.

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