CYTOKINE REGULATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENTRY AND REPLICATION IN HUMAN MONOCYTES MACROPHAGES THROUGH MODULATION OF CCR5 EXPRESSION/

Human macrophages express chemokine receptors that act as coreceptors for human immunodeficiency virus type 1 (HIV-1) and are major targets for HIV-1 infection in vivo. The effects of cytokines on HIV-1 infecti on of macrophages and on the expression of CCR5, the principal corecep tor for macrophage-tropic viruses, have now been investigated. Express ion of CCR5 on the surface of freshly isolated human monocytes was vir tually undetectable by flow cytometry with the monoclonal antibody 5C7 . However, after culture of monocytes for 48 h in serum-free medium, a pproximately 30% of the resulting macrophages expressed CCR5 and the c ells were susceptible to infection by macrophage-tropic HIV-1. Additio n of either macrophage colony-stimulating factor (M-CSF) or granulocyt e-macrophage colony-stimulating factor (GM-CSF) to the cultures marked ly increased both the extent of HIV-1 entry and replication as well as surface expression of CCR5. In contrast, addition of the T-helper 2 ( Th2) cell-derived cytokine interleukin-il (IL-4) or IL-13 prevented th e expression of CCR5 induced by culture in medium alone, and IL-il inh ibited virus entry, replication, and cytopathicity under these conditi ons. IL-4 or IL-13 also prevented the stimulatory effects of M-CSF or GM-CSF on CCR5 expression as well as HIV-1 entry and replication. In a ddition, IL-10 reversed the increase in CCR5 expression induced by pre treatment of cells with M-CSF. Although IL-10 also inhibits HIV-1 repl ication in macrophages, it did not suppress surface CCR5 expression in duced by colony-stimulating factors. These results indicate that the c ytokine environment determines the susceptibility of macrophages to HI V-1 infection by various mechanisms, one of which is the regulation of HIV-1 coreceptor expression.