TI  -  <prot>CCR5</prot>  binds multiple CC-chemokines:  <prot>MCP-3</prot>  acts as a natural antagonist.
PG  - 1899-905
AB  -    <prot>CCR5</prot>    was first characterized as a receptor for  <prot>MIP-1alpha</prot> ,  <prot>MIP-1beta</prot> , and
       <prot>RANTES</prot> , and was rapidly shown to be the main coreceptor for M-tropic human
      immunodeficiency virus (HIV)-1 strains and simian immunodeficiency virus
      (SIV). Chemokines constitute a rapidly growing family of proteins and
      receptor-chemokine interactions are known to be promiscuous and redundant.
      We have therefore tested whether other CC-chemokines could bind to and
      activate <prot>CCR5</prot>. All CC-chemokines currently available were tested for their
      ability to compete with [(125)I]-<prot>MIP-1beta</prot> binding on a stable cell line
      expressing recombinant <prot>CCR5</prot>, and/or to induce a functional response in
      these cells. We found that in addition to  <prot>MIP-1beta</prot> ,  <prot>MIP-1alpha</prot> , and
       <prot>RANTES</prot> , five other CC-chemokines could compete for [(125)I]-   <prot>MIP-1beta</prot>   
      binding: <prot>MCP-2</prot>, <prot>MCP-3</prot>, <prot>MCP-4</prot>, <prot>MCP-1</prot>, and <prot>eotaxin</prot> binding was characterized
      by IC(50) values of 0.22, 2.14, 5.89, 29.9, and 21.7 nmol/L, respectively.
      Among these ligands,  <prot>MCP-3</prot>  had the remarkable property of binding  <prot>CCR5</prot> 
      with high affinity without eliciting a functional response, <prot>MCP-3</prot> could
      also inhibit the activation of <prot>CCR5</prot> by <prot>MIP-1beta</prot> and may therefore be
      considered as a natural antagonist for <prot>CCR5</prot>. It was unable to induce
      significant endocytosis of the receptor. Chemokines that could compete
      with high affinity for <prot>MIP-1beta</prot> binding could also compete for monomeric
      <prot>gp120</prot> binding, although with variable potencies; maximal   <prot>gp120</prot>   binding
      inhibition was 80% for  <prot>MCP-2</prot> , but only 30% for  <prot>MIP-1beta</prot> .  <prot>MCP-3</prot>  could
      compete efficiently for  <prot>gp120</prot>  binding but was, however, found to be a weak
      inhibitor of HIV infection, probably as a consequence of its inability to
      downregulate the receptor.
AD  - IRIBHN and Service de Genetique Medicale, Universite Libre de Bruxelles,
