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Prediction of HIV-1 Coreceptor Usage (Tropism) by Sequence Analysis using a Genotypic Approach
07:06

Prediction of HIV-1 Coreceptor Usage (Tropism) by Sequence Analysis using a Genotypic Approach

Published on: December 1, 2011

Two novel fully functional isoforms of CX3CR1 are potent HIV coreceptors

Alexandre Garin1, Nadine Tarantino, Sophie Faure

  • 1Laboratoire d'Immunologie Cellulaire et Tissulaire, Institut National de la Santé et de la Recherche Médicale, Unité 543, Hôpital Pitié-Salpêtriere, Paris, France.

Journal of Immunology (Baltimore, Md. : 1950)
|November 11, 2003
PubMed

Insights

Two new forms of the human chemokine receptor CX3CR1 were found. These extended isoforms show increased sensitivity to CX3CL1 and HIV, impacting immune cell activation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Chemokine receptors play crucial roles in immune cell trafficking and activation.
  • CX3CR1 (fractalkine receptor) is a key chemokine receptor involved in immune responses.
  • Alternative splicing can generate diverse protein isoforms with potentially distinct functions.

Purpose of the Study:

  • To identify and characterize novel isoforms of the human chemokine receptor CX3CR1.
  • To investigate the functional differences between standard and extended CX3CR1 isoforms.
  • To assess the impact of N-terminal extensions on CX3CR1 ligand binding, signaling, and HIV coreceptor activity.

Main Methods:

  • Identification of novel CX3CR1 isoforms via alternative splicing.
  • Expression of CX3CR1 isoforms in HEK-293 cells.
  • Ligand binding assays (steady-state and kinetic) with CX3CL1.
  • Agonist-induced calcium mobilization assays.
  • Chemotaxis assays.
  • HIV fusion and infection assays.

Main Results:

  • Two novel CX3CR1 isoforms with extended N-terminal regions (7 and 32 amino acids) were identified.
  • Expression levels of these isoforms varied across immune cell types (monocytes, NK cells, CD4+ T lymphocytes).
  • Extended isoforms exhibited altered kinetics of CX3CL1 binding (higher k(on) and k(off)).
  • All isoforms bound CX3CL1 with similar affinity, but extended isoforms showed enhanced signaling (lower EC50) and chemotaxis.
  • Novel CX3CR1 isoforms demonstrated increased potency as HIV coreceptors.

Conclusions:

  • Two novel, functionally distinct CX3CR1 isoforms generated by alternative splicing were characterized.
  • N-terminal extensions in CX3CR1 isoforms modulate ligand binding kinetics and enhance cellular responses to CX3CL1.
  • These extended CX3CR1 isoforms exhibit increased sensitivity and potency, including as HIV coreceptors.
  • The findings reveal new complexity in CX3CR1-mediated cell activation and highlight the importance of the N-terminal domain in chemokine receptor function.

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