Vaccinia virus activation of CCR5 invokes tyrosine phosphorylation signaling events that support virus replication

J Virol. 2006 Jul;80(14):7245-59. doi: 10.1128/JVI.00463-06.

Abstract

Vaccinia virus, a poxvirus, produces structurally distinct forms of virions for which the immediate events following cell entry are ill-defined. We provide evidence that intracellular mature virus (IMV) enters both permissive and nonpermissive T-cell lines and that introduction of CCR5 into nonpermissive mouse fibroblasts or human primary T cells renders the cells permissive for vaccinia replication. Notably, T cells expressing CCR5 in which tyrosine 339 in the intracellular region is replaced by phenylalanine no longer support virus replication or virus-inducible activation of specific host cell signaling effectors IRS-2, Grb2, and Erk1/2. We show that following IMV entry into the cell, the intact but not the tyrosine-deficient CCR5 is rapidly internalized and colocalizes with virus. This colocalization precedes virus-inducible signaling and replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Fibroblasts / metabolism*
  • Fibroblasts / virology
  • GRB2 Adaptor Protein / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NIH 3T3 Cells
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Point Mutation
  • Protein Processing, Post-Translational / genetics
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism*
  • Signal Transduction*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / virology
  • Tyrosine / genetics
  • Tyrosine / metabolism
  • Vaccinia / genetics
  • Vaccinia / metabolism
  • Vaccinia virus / physiology*
  • Virus Replication / physiology*

Substances

  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Phosphoproteins
  • Receptors, CCR5
  • Tyrosine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3