Immunomodulation by herpesvirus U51A chemokine receptor via CCL5 and FOG-2 down-regulation plus XCR1 and CCR7 mimicry in human leukocytes

Eur J Immunol. 2008 Mar;38(3):763-77. doi: 10.1002/eji.200737618.

Abstract

Human herpesvirus-6A (HHV-6A) betachemokine-receptor U51A binds inflammatory modulators CCL2, CCL5, CCL11, CCL7, and CCL13. This unique specificity overlaps that of human chemokine receptors CCR1, CCR2, CCR3, and CCR5. In model cell lines, expression leads to CCL5 down-regulation with both constitutive and inducible signaling. Here, immunomodulation pathways are investigated in human leukocytes permissive for infection. Constitutive signaling was shown using inositol phosphate assays and inducible calcium signaling by response to CCL2, CCL5 and CCL11. Constitutive signaling targets were examined using an immune response-related microarray and RT-PCR, showing down-regulation of CCL5 and FOG-2, a hematopoietic transcriptional repressor. By RT-PCR and siRNA reversion, CCL5 and FOG-2 were shown down-regulated, during peak U51A expression post infection. Two further active ligands, XCL1 and CCL19, were identified, making U51A competitor to their human receptors, XCR1 and CCR7, on T lymphocytes, NK and dendritic cells. Finally, U51A-expressing cell lines and infected ex vivo leukocytes, showed migration towards chemokine-gradients, and chemokine internalization. Consequently, U51A may affect virus dissemination or host transmission by chemotaxis of infected cells to sites of chemokine secretion specific for U51A (for example the lymph node or lung, by CCL19 or CCL11, respectively) and evade immune-effector cells by chemokine diversion and down-regulation, affecting virus spread and inflammatory pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Chemokine CCL11 / pharmacology
  • Chemokine CCL19 / metabolism
  • Chemokine CCL19 / pharmacology
  • Chemokine CCL2 / metabolism
  • Chemokine CCL2 / pharmacology
  • Chemokine CCL5 / genetics*
  • Chemokine CCL5 / pharmacology
  • Chemokines / metabolism
  • Chemokines / pharmacology
  • Chemokines, C / metabolism
  • Chemokines, C / pharmacology
  • Chemotaxis / drug effects
  • Chemotaxis / immunology
  • DNA-Binding Proteins / genetics*
  • Down-Regulation / genetics
  • Endocytosis / drug effects
  • Endocytosis / immunology
  • Herpesvirus 6, Human / immunology
  • Humans
  • Inositol Phosphates / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism*
  • Leukocytes, Mononuclear / virology
  • Molecular Mimicry
  • RNA, Small Interfering / genetics
  • Receptors, CCR7 / genetics*
  • Receptors, Chemokine / agonists
  • Receptors, Chemokine / physiology*
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, Virus / agonists
  • Receptors, Virus / physiology*
  • Transcription Factors / genetics*

Substances

  • CCL11 protein, human
  • CCL19 protein, human
  • CCL2 protein, human
  • CCL5 protein, human
  • CCR7 protein, human
  • Chemokine CCL11
  • Chemokine CCL19
  • Chemokine CCL2
  • Chemokine CCL5
  • Chemokines
  • Chemokines, C
  • DNA-Binding Proteins
  • Inositol Phosphates
  • RNA, Small Interfering
  • Receptors, CCR7
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • Receptors, Virus
  • Transcription Factors
  • U51 protein, human herpesvirus 6
  • XCL1 protein, human
  • XCR1 protein, human
  • ZFPM2 protein, human