Oligomerization of the Macrophage Mannose Receptor Enhances gp120-mediated Binding of HIV-1

Abstract

C-type lectin receptors expressed on the surface of dendritic cells and macrophages are able to bind glycoproteins of microbial pathogens via mannose, fucose, and N-acetylglucosamine. Langerin on Langerhans cells, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin on dendritic cells, and mannose receptor (MR) on dendritic cells and macrophages bind the human immunodeficiency virus (HIV) envelope protein gp120 principally via high mannose oligosaccharides. These C-type lectin receptors can also oligomerize to facilitate enhanced ligand binding. This study examined the effect of oligomerization of MR on its ability to bind to mannan, monomeric gp120, native trimeric gp140, and HIV type 1 BaL. Mass spectrometry analysis of crosslinked MR showed homodimerization on the surface of primary monocyte-derived dendritic cells and macrophages. Both monomeric and dimeric MR were precipitated by mannan, but only the dimeric form was co-immunoprecipitated by gp120. These results were confirmed independently by flow cytometry analysis of soluble monomeric and trimeric HIV envelope and a cellular HIV virion capture assay. As expected, mannan bound to the carbohydrate recognition domains of MR dimers mostly in a calcium-dependent fashion. Unexpectedly, gp120-mediated binding of HIV to dimers on MR-transfected Rat-6 cells and macrophages was not calcium-dependent, was only partially blocked by mannan, and was also partially inhibited by N-acetylgalactosamine 4-sulfate. Thus gp120-mediated HIV binding occurs via the calcium-dependent, non-calcium-dependent carbohydrate recognition domains and the cysteine-rich domain at the C terminus of MR dimers, presenting a much broader target for potential inhibitors of gp120-MR binding.

Inhibition of Two Temporal Phases of HIV-1 Transfer from Primary Langerhans Cells to T Cells: The Role of Langerin

“…Because oligomerization of CLRs such as DC-SIGN (37-39) and MR (40,41) has been reported to be essential for the binding of oligosaccharide ligands, we showed that native trimeric HIV envelope protein (HIV AD8 gp140) and HIV BaL particles bound strongly to langerin trimers on Mutz-3 LCs, suggesting that soluble langerin homologs may need to be trimeric for maximal inhibition. Thus, we examined inhibition of HIV binding to langerin on eLCs and subsequent firstand second-phase viral transfer to T cells with a langerin-specific mAb and by langerin homologs consisting of soluble trimeric fulllength extracellular domain (ECD) or the monomeric truncated carbohydrate recognition domain (CRD).…”

Timing of Galectin-1 Exposure Differentially Modulates Nipah Virus Entry and Syncytium Formation in Endothelial Cells

“…For example, mannan-binding lectin, a soluble innate immune lectin, binds to influenza A virus and leads directly to virus inactivation (43). In contrast, another mannose-binding human lectin, macrophage mannose receptor (MMR) potentiates HIV binding to target cells (44)(45)(46), and MMR can also potentiate infection of macrophages by influenza virus (47), so that different mannose-binding lectins can bind to viruses to either reduce or potentiate infection. Considering the long-standing evolutionary relationship between virus and host, it is not entirely surprising that viruses have learned to co-opt host innate immune defenses for increased target cell entry and replication.…”

Measuring Inequalities in Gene Co-expression Networks of HIV-1 Infection Using the Lorenz Curve and Gini Coefficient

“…Second, the delta Gini is valuable to identify candidate biomarkers of HIV-1 with low rank of dC values. For instance, MRC1 is a mannose receptor interacting with several HIV proteins to promote viral spread [13][14][15], and has a delta Gini value of -0.44 (rank=2) and a dC value of 0.96 (rank=173) while comparing networks constructed for patients at the AIDS stage and for uninfected subjects. Similarly, PPFIBP1, which plays roles in HIV-1 replication, also has a high rank of delta Gini (value=-0.42; rank=3) but a low rank of dC (value=0.89; rank=283).…”