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Thioredoxin (Trx1) regulates CD4 membrane domain localization and is required for efficient CD4-dependent HIV-1 entry

Naazneen Moolla1, Mark Killick1, Maria Papathanasopoulos1

  • 1HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Faculty of Health Sciences, 7 York Road Parktown, 2193 Johannesburg, South Africa.

Biochimica Et Biophysica Acta
|May 29, 2016
PubMed

Insights

Extracellular redox conditions regulate CD4 localization into membrane domains, impacting T cell activation and HIV entry. This finding reveals a novel mechanism for controlling immune cell function and viral replication.

Area of Science:

  • Immunology
  • Cell Biology
  • Virology

Background:

  • CD4 glycoprotein on immune cells is crucial for T cell activation by co-engaging MHC and TCR.
  • CD4's dynamic localization into membrane microdomains influences its function and HIV replication efficiency.
  • Mechanisms regulating CD4 localization and its biological significance remain incompletely understood.

Purpose of the Study:

  • To investigate the dynamic redox-dependent effects on CD4 membrane domain localization.
  • To elucidate the role of extracellular redox environment in regulating CD4 function.

Main Methods:

  • Confocal microscopy, density-gradient centrifugation, and flow cytometry were employed.
  • Analysis focused on dynamic redox-dependent effects on CD4 membrane domain localization.

Main Results:

  • Blocking cell surface redox exchanges with DTNB or Trx1 inhibitors induced CD4 translocation into detergent-resistant membrane domains (DRM).
  • This effect was specific to CD4, as CCR5 localization remained unchanged upon Trx1 inactivation.
  • DTNB treatment and Trx1 depletion significantly inhibited CD4-dependent HIV entry but only moderately affected CD4-independent HIV pseudovirion infectivity.

Conclusions:

  • Extracellular redox environment changes, possibly via disulfide bond oxidoreduction, signal CD4 translocation into DRM clusters.
  • This CD4 sequestration into DRM is a potential mechanism underlying the anti-HIV effects of cell surface oxidoreductase inhibition.
  • Extracellular redox conditions regulate CD4 function by altering its membrane domain localization.
Abstract

Keywords:
CD4HIV-1Lipid raftRedoxThioredoxin

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