HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling

Blood. 2012 Jan 19;119(3):786-97. doi: 10.1182/blood-2011-08-373209. Epub 2011 Nov 28.

Abstract

The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4(+) T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4(+) T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1-infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active Lck to the immunological synapse after TCR engagement and limiting signal initiation at the PM. Instead, Nef triggers Lck-dependent activation of TGN-associated Ras-Erk signaling to promote the production of the T lymphocyte survival factor IL-2 and to enhance virus spread. Overexpression of the Lck PM transporter Unc119 restores Nef-induced subversions of Lck trafficking and TCR signaling. Nef therefore hijacks Lck sorting to selectively activate TGN-associated arms of compartmentalized TCR signaling. By tailoring T-lymphocyte responses to antigenic stimulation, Nef optimizes the environment for HIV-1 replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / virology
  • Cell Communication
  • Enzyme-Linked Immunosorbent Assay
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / immunology
  • HIV-1 / metabolism
  • Humans
  • Immunological Synapses / physiology*
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Receptors, Antigen, T-Cell
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Virus Replication / immunology
  • nef Gene Products, Human Immunodeficiency Virus / immunology
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*
  • trans-Golgi Network / immunology*
  • trans-Golgi Network / metabolism
  • trans-Golgi Network / virology

Substances

  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • nef Gene Products, Human Immunodeficiency Virus
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)