Inhibition of HIV-1 infection by viral chemokine U83A via high-affinity CCR5 interactions that block human chemokine-induced leukocyte chemotaxis and receptor internalization.
HIV-1 strains use C-C-chemokine receptor 5, CCR5, as a coreceptor for host transmission. Human CCR5 chemokine ligands inhibit binding and infection, whereas CCR5 mutations also inhibit infection by preventing surface expression, resulting in delayed progression to AIDS. Here, we describe a human herpesvirus 6 (HHV-6A) chemokine, U83A, which binds CCR5 with higher affinity than human chemokines, displacing their binding and leading to inhibition of chemotaxis of human leukocytes. Similarly, U83A inhibits infection by HIV-1 strains which use CCR5, but not the CXCR4, coreceptor. Unlike human CCR5 chemokine ligands which induce rapid CCR5 internalization mediated via clathrin, treatment with U83A prevents internalization. A spliced truncated U83A isoform, U83A-N, also binds CCR5 albeit with lower affinity, and this correlates with lower HIV-1 infection inhibition, whereas further truncation abolishes binding and any inhibition. Confocal microscopy confirms CCR5 internalization inhibition by U83A treatment, whereas labeled transferrin uptake shows that endocytosis via clathrin is unaltered. Previous results show that, although U83A-N is an antagonist, U83A is an agonist for CCR1, CCR4, CCR6, and CCR8 present on immune effector and antigen-presenting cells and here also shown for CCR5. Thus, U83A could act as a novel inhibitor of HIV-1 infection while also stimulating local immunity to the virus.
Catusse
Julie
J
Pathogen Molecular Biology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, University of London, Keppel Street, London, UK.
Parry
Chris M
CM
Dewin
David R
DR
Gompels
Ursula A
UA
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D065100:CCR5 Receptor Antagonists; D019556:COS Cells; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000819:agonists* / Q000276:immunology; D019707:Receptors, Chemokine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
D065100:CCR5 Receptor Antagonists; D018925:Chemokines; D002966:Clathrin; D020033:Protein Isoforms; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; C120137:U83 protein, Human herpesvirus 6; D014764:Viral Proteins