Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection

J Exp Med. 2011 Aug 29;208(9):1823-34. doi: 10.1084/jem.20101805. Epub 2011 Aug 22.

Abstract

Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism*
  • Adult
  • Antiretroviral Therapy, Highly Active / methods
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Connexins / genetics
  • Connexins / metabolism
  • Drug Resistance, Viral / drug effects
  • Drug Resistance, Viral / genetics
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV-1 / physiology*
  • Humans
  • Male
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Receptors, Purinergic P2Y2 / genetics
  • Receptors, Purinergic P2Y2 / metabolism*
  • Signal Transduction
  • Virus Replication / drug effects
  • Virus Replication / genetics

Substances

  • Connexins
  • Nerve Tissue Proteins
  • PANX1 protein, human
  • Receptors, Purinergic P2Y2
  • Adenosine Triphosphate
  • Focal Adhesion Kinase 2