Soluble CD40 ligand induces beta-chemokine production by macrophages and resistance to HIV-1 entry.
CD40 ligand (CD40L) is a cell surface molecule of CD4(+)T cells that interacts with its receptor CD40 on antigen presenting cells to mediate thymus-dependent humoral immunity and inflammatory reactions. We report here that treating monocyte-derived macrophages (MDM) with a trimeric soluble form of CD40L (CD40LT) induced them to secrete high levels of the beta-chemokines RANTES, MIP-1alpha and MIP-1beta that are ligands for CCR5 and able to inhibit HIV-1 entry. CD40LT inhibited the entry of M-tropic HIV-1 reporter viruses. Furthermore, supernatants obtained from CD40LT-stimulated macrophages protected CEMx174-CCR5 cells from infection by HIV-1(JRFL)reporter virus. The inhibitory activity appeared to be due to beta-chemokines present in the supernatant, since pretreating them with a cocktail of antibodies to RANTES, MIP-1alpha and MIP-1beta neutralized the inhibitory activity of the supernatants. In addition, treating monocytes with CD40LT caused CCR5 and CD4 to be downregulated from the cell surface. In vivo, macrophages activated through CD40 could interfere with HIV replication.
di Marzio
P
P
Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Ave, New York, NY 10016, USA. pdimarzio@picower.edu
Mariani
R
R
Lui
R
R
Thomas
E K
EK
Landau
N R
NR
D015704:CD4 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism* / Q000821:virology*; D019713:Receptors, CCR5 / Q000378:metabolism; D014162:Transfection
D015704:CD4 Antigens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D023201:CD40 Ligand; D008156:Luciferases