DC-SIGN Mediates Cell-Free Infection and Transmission of Human T-cell Lymphotropic Virus Type 1 by Dendritic Cells

J Virol. 2009 Nov;83(21):10908-21. doi: 10.1128/JVI.01054-09. Epub 2009 Aug 19.

Abstract

Despite the susceptibility of dendritic cells (DCs) to human T-cell lymphotropic virus type 1 (HTLV-1) infection and the defined role of these cells in disease pathogenesis, the mechanisms of viral binding to DCs have not been fully delineated. Recently, a glucose transporter, GLUT-1, heparan sulfate proteoglycans (HSPGs), and neuropilin-1 (NRP-1) were demonstrated to facilitate HTLV-1 entry into T cells. DCs express their own array of antigen receptors, the most important being the DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) with respect to retrovirus binding. Consequently, the role of DC-SIGN and other HTLV-1 attachment factors was analyzed in viral binding, transmission, and productive infection using monocyte-derived DCs (MDDCs), blood myeloid DCs, and B-cell lines expressing DC-SIGN. The relative expression of DC-SIGN, GLUT-1, HSPGs, and NRP-1 first was examined on both DCs and B-cell lines. Although the inhibition of these molecules reduced viral binding, HTLV-1 transmission from DCs to T cells was mediated primarily by DC-SIGN. DC-SIGN also was shown to play a role in the infection of MDDCs as well as model B-cell lines. The HTLV-1 infection of MDDCs also was achieved in blood myeloid DCs following the enhancement of virus-induced interleukin-4 production and subsequent DC-SIGN expression in this cell population. This study represents the first comprehensive analysis of potential HTLV-1 receptors on DCs and strongly suggests that DC-SIGN plays a critical role in HTLV-1 binding, transmission, and infection, thereby providing an attractive target for the development of antiretroviral therapeutics and microbicides.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / immunology*
  • Cells, Cultured
  • Dendritic Cells* / metabolism
  • Dendritic Cells* / virology
  • Gene Products, env / genetics
  • Gene Products, env / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Heparan Sulfate Proteoglycans / metabolism
  • Human T-lymphotropic virus 1* / immunology
  • Human T-lymphotropic virus 1* / pathogenicity
  • Humans
  • Interleukin-4 / immunology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Retroviridae Proteins, Oncogenic / genetics
  • Retroviridae Proteins, Oncogenic / metabolism
  • Virus Attachment
  • Virus Internalization
  • Virus Replication

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Gene Products, env
  • Glucose Transporter Type 1
  • Heparan Sulfate Proteoglycans
  • Lectins, C-Type
  • Receptors, Cell Surface
  • Retroviridae Proteins, Oncogenic
  • gp46 protein, Human T-cell leukemia virus type I
  • Neuropilin-1
  • Interleukin-4