A systems analysis of dendritic cell interactions with HIV-1 during cell-cell transmission : a focus on cytokines, chemokines and receptors

The propagation of HIV-1 is driven by mechanisms of innate immune evasion, a phenomenon observed in dendritic cells (DCs) and their subsets, one of the earliest cell types likely to encounter HIV-1 during acute infection. Infected DCs are capable of highly effective viral transfer to target CD4+ T-cells across the virological synapse (VS), a specialised virus-induced cell junction, which enables rapid viral dissemination and accelerates disease progression. Previous studies have implicated a major role for cytokines and chemokines in the infection of DC subsets, though their functions are yet to be fully characterised. Integrative, data-driven approaches to disease biology have become central to understanding systems-level processes. In this study, we used high-throughput RNAi screening techniques using the On-Target SMARTpool cytokine/chemokine siRNA library of 319 genes to screen for the differential effects on HIV-1 viral transfer from monocyte-derived DCs to CD4+ Tcells. Our screen highlights a potent restrictive role for the cytokine-mediator protein, Macrophage MigrationInhibitoryFactor(MIF)duringHIV-1trans-infection. TheactivitiesofMIFwerevalidated using three key loss-of-function assays including genetic downregulation, neutralisation by biologics and pharmacological inhibition in trans- to both SupT1 cell lines and autologous CD4+ T-cells. FurtherinvestigationsfoundthatMIFregulatesautophagyinMDDCwhichhasbeenpreviously been described as a protective mechanism against infection by HIV-1. Loss of MIF was associated with impaired LC3+ autophagosome formation, leading to intracellular accumulation of virus and enhanced capacity for cell-cell transfer. These findings bridge an important gap between the cytokine network and autophagy which will inform therapeutic strategies against HIV-1 infection and transmission.