Human primary macrophages derived in vitro from circulating monocytes comprise adherent and non-adherent subsets with differential expression of siglec-1 and CD4 and permissiveness to HIV-1 infection

Macrophages are a major target for human immunodeficiency virus type 1 (HIV-1) infection. However, macrophages are largely heterogeneous and may exhibit differences in permissiveness to HIV-1 infection. This study highlights the interplay of macrophage heterogeneity in HIV-1 pathogenesis. We show that monocyte-derived macrophages (MDMs) could be divided into two distinct subsets: CD14⁺Siglec-1^hiCD4⁺ (non-adherent MDM) and CD14⁺Siglec-1^LoCD4^- (adherent MDM). The CD14⁺Siglec-1hiCD4⁺MDM subset represented the smaller proportion in the macrophage pool, and varied among different donors. Fractionation and subsequent exposure of the two MDM subsets to HIV-1 revealed opposite outcomes in terms of HIV-1 capture and infection. Although the CD14⁺Siglec-1^hiCD4⁺MDM captured significantly more HIV-1, infection was significantly higher in the CD14⁺Siglec-1^LoCD4-MDM subset. Thus, CD14⁺Siglec-1^hiCD4⁺MDM were less permissive to infection. Depletion of CD14⁺Siglec-1^hiCD4⁺MDM or a decrease in their percentage, resulted in increased infection of MDM, suggestive of a capacity of these cells to capture and sequester HIV-1 in an environment that hinders its infectivity. Increased expression of innate restriction factors and cytokine genes were observed in the non-adherent CD14⁺Siglec-1^hiCD4⁺MDM, both before and after HIV-1 infection, compared to the adherent CD14⁺Siglec-1^LoCD4^-MDM. We speculate that the differential expression of gene expression profiles in the two macrophage subsets may provide an explanation for the differences observed in HIV-1 infectivity.