Human interleukin‐34‐derived macrophages have increased resistance to HIV‐1 infection
HighlightsHuman macrophages differentiated by the M‐CSF are susceptible to HIV‐1.Macrophages differentiated by the IL‐34 are much more resistant to HIV‐1.The two populations express comparable surface levels of CD4 and CCR5.IL‐34 macrophages express significantly greater levels of pertinent restriction factor genes. Abstract The establishment of latent HIV‐1 reservoirs in terminally differentiated cells represents a major impediment to the success of antiretroviral therapies. Notably, macrophages (M&phgr;s) are susceptible to HIV‐1 infection and recent evidence suggests that they may be involved in long‐term HIV‐1 persistence. While the extensive functional heterogeneity seen across the M&phgr; cell lineage parallels the spectrum of HIV‐1 susceptibility reported across these cell subsets, the facets of M&phgr; HIV‐1 resistance and susceptibility remain to be fully defined. Notably, the differentiation of most M&phgr; subsets depends on signaling through the macrophage colony‐stimulating factor receptor (M‐CSFR), which in addition to M‐CSF, is now known to bind the unrelated interleukin‐34 (IL‐34) cytokine. The biological need for two M‐CSFR ligands awaits full elucidation. Here, we report that M&phgr;s differentiated from human peripheral blood monocytes with IL‐34 are substantially more resistant to HIV‐1 infection than M‐CSF‐derived M&phgr;s. Moreover, while both M&phgr; subsets express comparable surface protein levels of the HIV‐1 receptor and co‐receptor, CD4 and CCR5 respectively, the IL‐34‐M&phgr;s express significantly greater levels of pertinent restriction factor genes, potentially accounting for their greater resistance to HIV‐1 infection than that observed in M‐CSF‐M&phgr;s. Together, our findings underline previously unexplored differentiation pathways resulting in HIV‐1‐susceptible and resistant M&phgr; subsets and pave the way for further research that may overcome one of the last major hurdles in developing more successful antiretroviral therapy.