Tissue‐like environments shape functional interactions of HIV‐1 with immature dendritic cells

Immature dendritic cells (iDCs) migrate in microenvironments with distinct cell and extracellular matrix densities in vivo and contribute to HIV‐1 dissemination and mounting of antiviral immune responses. Here, we find that, compared to standard 2D suspension cultures, 3D collagen as tissue‐like environment alters iDC properties and their response to HIV‐1 infection. iDCs adopt an elongated morphology with increased deformability in 3D collagen at unaltered activation, differentiation, cytokine secretion, or responsiveness to LPS. While 3D collagen reduces HIV‐1 particle uptake by iDCs, fusion efficiency is increased to elevate productive infection rates due to elevated cell surface exposure of the HIV‐1‐binding receptor DC‐SIGN. In contrast, 3D collagen reduces HIV transfer to CD4 T cells from iDCs. iDC adaptations to 3D collagen include increased pro‐inflammatory cytokine production and reduced antiviral gene expression in response to HIV‐1 infection. Adhesion to a 2D collagen matrix is sufficient to increase iDC deformability, DC‐SIGN exposure, and permissivity to HIV‐1 infection. Thus, mechano‐physical cues of 2D and 3D tissue‐like collagen environments regulate iDC function and shape divergent roles during HIV‐1 infection.