HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits

Nat Immunol. 2009 Sep;10(9):1008-17. doi: 10.1038/ni.1753. Epub 2009 Aug 2.


Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.

Publication types

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

MeSH terms

  • Actins / metabolism
  • B-Lymphocytes / metabolism*
  • CD40 Antigens / physiology
  • Cell Communication*
  • Germinal Center / physiology
  • HIV Antibodies / immunology*
  • HIV Core Protein p24 / physiology
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin A / immunology*
  • Immunoglobulin Class Switching
  • Immunoglobulin G / immunology*
  • Macrophages / virology
  • U937 Cells
  • nef Gene Products, Human Immunodeficiency Virus / physiology*


  • Actins
  • CD40 Antigens
  • HIV Antibodies
  • HIV Core Protein p24
  • Immunoglobulin A
  • Immunoglobulin G
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1
  • p24 protein, Human Immunodeficiency Virus Type 1