Alarmin S100A9 restricts retroviral infection by limiting reverse transcription in human dendritic cells

Dendritic cells (DC) subsets, like Langerhans cells (LC), are immune cells involved in pathogen sensing. They express specific antimicrobial cellular factors that are able to restrict infection and limit further pathogen transmission. Here, we identify the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte‐derived and skin‐derived LC. The intracellular expression of S100A9 is decreased upon LC maturation and inversely correlates with enhanced susceptibility to HIV‐1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV‐1 restriction while ectopic expression of S100A9 in various cell lines promotes intrinsic resistance to both HIV‐1 and MLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription. S100A9 also shows potent inhibitory effect against HIV‐1 and MMLV reverse transcriptase (RTase) activity in vitro in a divalent cation‐dependent manner. Our findings uncover an unexpected intracellular function of the human alarmin S100A9 in regulating antiretroviral immunity in Langerhans cells. Synopsis Human Langerhans cells (LC) are known to be refractory to HIV‐1 infection, however precise mechanisms remain unknown. Here we show that human S100A9 inhibits HIV‐1 infection of human LC at the reverse transcription step of the viral replication cycle. The activity of the HIV‐1 reverse transcriptase is decreased in vitro and ex vivo in presence of S100A9 in a Mg 2+ ‐dependent manner suggestive of a mechanism involving S100A9‐mediated chelation of divalent cations. TGF‐β modulates the expression and subcellular localization of S100A9 in myeloid‐derived cells. Endogenous S100A9 expression in human Langerhans cells limits HIV‐1 infection. S100A9 ectopic expression restricts infection by HIV‐1 and other retroviruses. The presence of S100A9 inhibits reverse transcriptase activity ex vivo and in vitro . The S100A9‐mediated antiviral activity is regulated in a Mg 2+ ‐dependent manner. Graphical Abstract Human Langerhans cells are refractory to HIV‐1 infection due to the expression of the alarmin S100A9 that inhibits reverse transcriptase activity.