Granulocyte-macrophage colony-stimulating factor inhibits HIV-1 replication in monocyte-derived macrophages

Background: Previous studies of the effect of granulocyte-macrophage colony -stimulating factor (GM-CSF) on HIV-1 replication in macrophages have had i nconsistent results, variously reporting no effect, augmentation or inhibit ion of viral replication. Objective: To investigate the regulation of HIV-1 in monocyte-derived macro phages (MDM) by CM-CSF in vitro. Methods: The role of GM-CSF on HIV-1 replication was assessed as supernatan t and intracellular p24 antigen concentrations and by HIV-1 DNA and mRNA pr oduction under different culture conditions. Expression of CD4 and CCR5 rec eptors was examined. The effect of CM-CSF with an E21R mutation, which bind s only to the alpha-chain of CM-CSF receptor, was used as an additional con trol. Results: CM-CSF consistently suppressed HIV-1 replication in human MDM in v itro, as assessed by supernatant and intracellular p24 antigen concentratio ns and HIV-1 gag mRNA expression. The inhibitory effect of GM-CSF on HIV-1 replication was observed regardless of HIV-1 strain, source of GM-CSF, stag e of MDM maturation or timing of GM-CSF exposure in relation to HIV-1 infec tion. The effect was dose dependent and reversed by addition of a neutraliz ing monoclonal antibody (4D4). Flow cytometric analysis of surface expressi on of CD4 and CCR5 indicates that CM-CSF: does nor affect HIV-1 entry into MDM. Analysis of intracellular HIV-1 DNA and mRNA suggests that HIV-1 repli cation is inhibited at or before transcription. E21R GM-CSF had no effect o n HIV-1 replication in MDM. Conclusions: CM-CSF regulates HIV-1 replication in MDM, inhibiting HIV-1 re plication through binding to the beta-chain of the GM-CSF receptor. (C) 200 0 Lippincott Williams & Wilkins.