Blood Journal
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Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity

  1. Kenjiro Tadagaki13,
  2. Daniela Tudor13,
  3. Florence Gbahou13,
  4. Pia Tschische4,
  5. Maria Waldhoer4,
  6. Morgane Bomsel13,
  7. Ralf Jockers13, and
  8. Maud Kamal13
  1. 1Inserm, U1016, Institut Cochin, Paris, France;
  2. 2Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, Paris, France;
  3. 3University Paris Descartes, Sorbonne Paris Cité, Paris, France; and
  4. 4Institute for Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria

Abstract

Human cytomegalovirus (HCMV) encodes four 7-transmembrane-spanning (7TM) proteins, US28, US27, UL33, and UL78, which present important sequence homology with human chemokine receptors. Whereas US28 binds a large range of chemokines and disturbs host cell signaling at different levels, the others are orphans with largely unknown functions. Assembly of 2 different 7TM proteins into hetero-oligomeric complexes may profoundly change their respective functional properties. We show that HCMV-encoded UL33 and UL78 form heteromers with CCR5 and CXCR4 chemokine receptors in transfected human embryonic kidney 293T cells and monocytic THP-1 cells. Expression of UL33 and UL78 had pleiotropic, predominantly negative, effects on CCR5 and CXCR4 cell surface expression, ligand-induced internalization, signal transduction, and migration without modifying the chemokine binding properties of CCR5 and CXCR4. Importantly, the coreceptor activity of CCR5 and CXCR4 for HIV was largely impaired in the presence of UL33 and UL78 without affecting expression of the primary HIV entry receptor CD4 and its interaction with CCR5 and CXCR4. Collectively, we identified the first molecular function for the HCMV-encoded orphan UL33 and UL78 7TM proteins, namely the regulation of cellular chemokine receptors through receptor heteromerization.

  • Submitted August 9, 2011.
  • Accepted March 14, 2012.
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