At mucosal surfaces, immature resident Dendritic Cells, Langerhans Cells and their subsets are the first cell types to encounter HIV-1 virus. During the early stages of infection, dendritic cells sense the virus through innate immune mechanisms inducing maturation and activating adaptive immune responses. HIV-1 subverts the immune system by hijacking dendritic cells, impairing cellular function to promote survival and propagation by trans-infection to target CD4 T-cells across the virological synapse. In a well-established model of cell-to-cell HIV-1 transfer from monocyte-derived DCs to CD4 T-cells, we have evaluated the molecular contribution of cytokines and cytokine receptors during the transfer of HIV-1 virus from DCs to CD4 T cells using a high-throughput siRNA library. Here we show that when macrophage migration inhibitory factor (MIF) is disrupted, the dynamics of HIV-1 trans-infection from DCs to T cells are greatly affected, making it a restrictive cytokine. We report a critical link between MIF expression in dendritic cells and autophagy. We show that the formation of LC3+ autophagosomes is a MIF-dependent process, required for the clearance of intracellular virus by selective degradation. Thus, the regulation of MIF expression in dendritic cells is critical in the induction of autophagy during HIV-1 infection, thereby reducing HIV-1 transmission from DC to CD4+ T cells, one of its earliest steps of entry in the host.
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