High-multiplicity HIV-1 infection and neutralizing antibody evasion mediated by the macrophage-T cell virological synapse

J Virol. 2014 Feb;88(4):2025-34. doi: 10.1128/JVI.03245-13. Epub 2013 Dec 4.

Abstract

Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based coculture model, we show that monocyte-derived macrophages (MDM) efficiently transmit a high-multiplicity HIV-1 infection to autologous CD4(+) T cells through a viral envelope glycoprotein (Env) receptor- and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. Virological synapse (VS)-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1 to 2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNMAbs) but shows resistance to bNMAbs targeting the Env gp41 subunit membrane-proximal external region (MPER). These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNMAb activity in HIV-1 prophylaxis and therapy. IMPORTANCE The ability of HIV-1 to move directly between contacting immune cells allows efficient viral dissemination with the potential to evade antibody attack. Here, we show that HIV-1 spreads from infected macrophages to T cells via a structure called a virological synapse that maintains extended contact between the two cell types, allowing transfer of multiple infectious events to the T cell. This process allows the virus to avoid neutralization by a class of antibody targeting the gp41 subunit of the envelope glycoproteins. These results have implications for viral spread in vivo and the specificities of neutralizing antibody elicited by antibody-based vaccines.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / immunology*
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology
  • DNA Primers / genetics
  • HIV Envelope Protein gp41 / immunology
  • HIV Infections / immunology
  • HIV Infections / transmission*
  • Immune Evasion / immunology*
  • Immunological Synapses / virology*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Luciferases
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Macrophages / immunology*
  • Macrophages / virology
  • Microscopy, Confocal
  • Neutralization Tests
  • Polymerase Chain Reaction
  • Time-Lapse Imaging

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • CD4 Antigens
  • DNA Primers
  • HIV Envelope Protein gp41
  • Lymphocyte Function-Associated Antigen-1
  • Intercellular Adhesion Molecule-1
  • Luciferases