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TR1.3 viral pathogenesis and syncytium formation are linked to Env-Gag cooperation

Samuel L Murphy1, Glen N Gaulton

  • 1The Children's Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, 354 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104-6142, USA.

Journal of Virology
|July 20, 2007
PubMed

Insights

Murine leukemia viruses (MLVs) TR1.3 and W102G cause severe neuropathology by inducing cell fusion. Both gag-dependent particle budding and p2E cleavage are essential for this syncytium-inducing phenotype, suggesting a fusion-from-without mechanism.

Area of Science:

  • Virology
  • Cell Biology
  • Neuroscience

Background:

  • Murine leukemia virus (MLV) infection, specifically strains TR1.3 and W102G, leads to severe neuropathology in vivo.
  • This neuropathology is characterized by extensive syncytia formation in brain capillary endothelial cells (BCECs) and cell fusion in resistant murine cell lines.
  • The virulence of these MLVs is linked to their env gene, but the precise mechanism of enhanced fusion remains unclear.

Purpose of the Study:

  • To investigate how syncytium-inducing (SI) TR1.3 and W102G MLVs overcome fusion inhibition mediated by the full-length Env cytoplasmic tail.
  • To determine the minimal functional requirements within gag-pol for the SI phenotype of these MLVs.

Main Methods:

  • Examined the capacity of TR1.3 and W102G MLVs to overcome fusion inhibitory activity of the Env cytoplasmic tail.
  • Assessed cell fusion in the presence of mutations disrupting p2E function.
  • Investigated the role of gag-pol coexpression and mutations within gag-pol in restoring and defining the SI phenotype.

Main Results:

  • TR1.3 and W102G Env proteins did not induce premature p2E cleavage or override p2E fusion inhibition in standard assays.
  • In cells with disrupted p2E function, TR1.3 and W102G Envs significantly enhanced cell fusion compared to non-SI MLV FB29.
  • TR1.3 and W102G Envs alone did not induce syncytia; coexpression with gag-pol restored syncytium formation.
  • Both gag-dependent particle budding and p2E cleavage were identified as necessary for activating the SI phenotype of TR1.3 and W102G viruses.

Conclusions:

  • The TR1.3 and W102G MLVs likely induce cell fusion through a fusion-from-without pathway.
  • Activation of the syncytium-inducing phenotype requires both gag-dependent particle budding and p2E cleavage.

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