Submitted August 21, 2006
Accepted December 20, 2006
Inhibition of HIV-1 infection by viral chemokine U83A via high affinity CCR5 interactions which block human chemokine-induced leukocyte chemotaxis and receptor internalisation
Julie Catusse, Chris M. Parry, David R. Dewin, and Ursula A. Gompels*
Pathogen Molecular Biology Unit, London School of Hygiene & Tropical Medicine, University of London, London, United Kingdom
University College London School of Medicine, University of London and Health Protection Agency, London, United Kingdom
* Corresponding author; email: ursula.gompels{at}lshtm.ac.uk.
HIV-1 strains utilise CC-chemokine receptor 5, CCR5, as a co-receptor for host transmission. Human CCR5 chemokine ligands inhibit binding and infection while 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, co-receptor. Unlike human CCR5 chemokine ligands which induce rapid CCR5 internalisation mediated via clathrin, treatment with U83A prevents internalisation. A spliced truncated U83A isoform, U83A-N, also binds CCR5 albeit with lower affinity and this correlates with lower HIV-1 infection inhibition, while further truncation abolishes binding and any inhibition. Confocal microscopy confirms CCR5 internalisation inhibition by U83A treatment while labelled transferrin uptake shows that endocytosis via clathrin is unaltered. Previous results show that while U83A-N is an antagonist, U83A is an agonist for CCR1, CCR4, CCR6 and CCR8 present on immune effector and antigen presenting cells; 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.
