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Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells

Edward P Browne1, Thomas Shenk

  • 1Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 16, 2003
PubMed

Insights

Human cytomegalovirus (CMV) protein pp65 blocks the innate immune response by inhibiting interferon (IFN) signaling. This viral protein antagonizes key transcription factors, preventing the induction of cellular antiviral genes.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Human cytomegalovirus (CMV) is a ubiquitous herpesvirus that can cause significant morbidity and mortality in immunocompromised individuals.
  • The innate immune system plays a critical role in controlling viral infections, with interferon (IFN)-responsive genes and chemokines being key components.
  • CMV has evolved mechanisms to evade or suppress host immune responses, but the precise molecular strategies remain under investigation.

Purpose of the Study:

  • To investigate the role of the CMV virion protein pp65 in modulating the innate immune response during early infection of fibroblasts.
  • To determine how pp65 affects the induction of IFN-responsive genes and proinflammatory chemokines.
  • To elucidate the impact of pp65 on the activity of key transcription factors involved in antiviral gene expression.

Main Methods:

  • Infection of human fibroblasts with wild-type and pp65-deficient CMV mutants.
  • Analysis of IFN signaling pathway activation and response to exogenous IFN.
  • DNA array analysis to assess the induction of cellular gene expression.
  • Electrophoretic mobility shift assays (EMSAs) to measure transcription factor DNA-binding activities (NF-kappaB, IRF1, ISGF3, IRF3).

Main Results:

  • CMV infection partially blocks the innate immune response, including the induction of IFN-responsive genes and chemokines.
  • The viral protein pp65, delivered in the virion, inhibits IFN signaling independently of de novo viral protein synthesis.
  • Infection with a pp65-deficient mutant virus resulted in significantly higher induction of IFN-response and chemokine RNAs compared to wild-type virus.
  • pp65 deficiency led to greater induction of NF-kappaB and IRF1 DNA-binding activities, while ISGF3 binding was modestly enhanced and IRF3 activity was unaffected.

Conclusions:

  • The CMV virion protein pp65 antagonizes an innate immune pathway involving NF-kappaB and IRF1.
  • pp65 actively suppresses the accumulation of mRNAs encoding cellular antiviral genes, contributing to viral immune evasion.
  • Understanding pp65's mechanism of immune antagonism is crucial for developing strategies to combat CMV infections.

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