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 inter acts with its receptor CD40 on antigen presenting cells to mediate thymus-d ependent humoral immunity and inflammatory reactions. We report here that t reating monocyte-derived macrophages (MDM) with a trimeric soluble form of CD40L (CD40LT) induced them to secrete high levels of the beta -chemokines RANTES, MIP-1 alpha and MIP-1 beta that are ligands for CCR5 and able to in hibit HIV-1 entry. CD40LT inhibited the entry of M-tropic HIV-1 reporter vi ruses. Furthermore, supernatants obtained from CD40LT-stimulated macrophage s 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 R ANTES, MIP-1 alpha and MIP-1 beta neutralized the inhibitory activity of th e supernatants, In addition, treating monocytes with CD40LT caused CCR5 and CD4 to be downregulated from the cell surface. In vivo, macrophages activa ted through CD40 could interfere with HIV replication. (C) 2000 Academic Pr ess.