HIV-1 Nef alters podosomes and promotes the mesenchymal migration in human macrophages.

Results Here, we examined the migration ability of HIV-1infected primary human macrophages. We show that HIV-1 infection modifies dramatically the migration of macrophages in 3-dimentionnal (3D) environments. While the amoeboid migration mode is inhibited upon infection, another migration mode specifically used by macrophages in dense 3D environments, the mesenchymal migration mode, is greatly enhanced. HIV-1 negative factor (Nef) is responsible for both effects on macrophage migration modes. Consistently with an increase in mesenchymal migration capacities, Nef accumulates around F-actin structures necessary for proteolysis of the extracellular matrix, e.g. podosomes, and alters their structure, function and dynamics. Mechanistically, HIV-1-induced podosome modifications and mesenchymal macrophage migration depend on Nef’s ability to activate the macrophage-specific Src tyrosine kinase, Hck.