HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread

Cell Rep. 2017 Jan 24;18(4):1062-1074. doi: 10.1016/j.celrep.2016.12.057.


HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways, we developed an approach to analyze the phosphoproteome in infected and uninfected mixed-population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1-induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of the T cell receptor were the most significantly activated, despite the absence of canonical antigen-dependent stimulation. The importance of this pathway was demonstrated by the depletion of proteins, and we show that HIV-1 Env-mediated cell-cell contact, the T cell receptor, and the Src kinase Lck were essential for signaling-dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a paradigm for antigen-independent T cell signaling.

Keywords: HIV; T cell; TCR; phosphoproteomics; signaling; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / immunology*
  • HEK293 Cells
  • HIV-1 / physiology*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Mass Spectrometry
  • Microscopy, Fluorescence
  • Phosphopeptides / analysis
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / virology
  • Virus Internalization
  • Virus Replication
  • src-Family Kinases / metabolism


  • Antigens, Viral
  • Phosphopeptides
  • Receptors, Antigen, T-Cell
  • src-Family Kinases