HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization.
The identification of the chemokine receptors as receptors for HIV-1 has boosted interest in these molecules, raising expectations for the development of new strategies to prevent HIV-1 infection. The discovery that chemokines block HIV-1 replication has focused attention on identifying their mechanism of action. Previous studies concluded that this inhibitory effect may be mediated by steric hindrance or by receptor down-regulation. We have identified a CCR5 receptor-specific mAb that neither competes with the chemokine for binding nor triggers signaling, as measured by Ca(2+) influx or chemotaxis. The antibody neither triggers receptor down-regulation nor interferes with the R5 JRFL viral strain gp120 binding to CCR5, but blocks HIV-1 replication in both in vitro assays using peripheral blood mononuclear cells as HIV-1 targets, as well as in vivo using human peripheral blood mononuclear cell-reconstituted SCID (severe combined immunodeficient) mice. Our evidence shows that the anti-CCR5 mAb efficiently prevents HIV-1 infection by inducing receptor dimerization. Chemokine receptor dimerization also is induced by chemokines and is required for their anti-HIV-1 activity. In addition to providing a molecular mechanism through which chemokines block HIV-1 infection, these results illustrate the prospects for developing new tools that possess HIV-1 suppressor activity, but lack the undesired inflammatory side effects of the chemokines.
Vila-Coro
A J
AJ
Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049, Madrid, Spain.
Mellado
M
M
Martín de Ana
A
A
Lucas
P
P
del Real
G
G
Martínez-A
C
C
Rodríguez-Frade
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018946:Chemokine CCL5; D019713:Receptors, CCR5