Mechanisms of cell-to-cell HIV-1 transfer toward macrophages. Three mechanisms are involved in macrophage infection by virus transfer from infected CD4⁺ T cells and their relative contribution is influenced by the macrophage activation status and the state of viability of the infected T cells. The synapse mode of infection becomes predominant in M1 macrophages but results in low permissiveness of macrophages to HIV-1 infection. The phagocytosis-mediated mechanism happens primarily when HIV-1-infected T cells are apoptotic and is poorly efficient for macrophage infection. The most productive viral infection of macrophages is observed through heterotypic cell fusion with viable infected T cells. This process occurs in several tissue-resident or infiltrated macrophage types and is negatively regulated by the CD81/RhoA-ROCK/Myosin II axis. This viral transmission route is promoted by an anti-inflammatory environment. Illustration by Claire Lastrucci.