As G5-DiMan here presents a good mimic for the HIV's trimeric gp120 spike, its stronger affinity with DC-SIGN over DC-SIGNR thus may help explain why DC-SIGN is more effective than DC-SIGNR in transmitting HIV infections. This result agreed well with our earlier results obtained with QD-DiMan and G5-DiMan conjugates. Given that the CRDs in DC-SIGN/R have the same mannosebinding motifs, the different affinities here may indicate that the DC-SIGN/R might adopt different modes in binding to Gx-DiMan, similar to those observed previously with QD-DiMan and G5-DiMan. (2) The MLGI affinity between Gx-DiMan and DC-SIGN/R increased significantly with the increasing GNP scaffold size. For example, the Kds for Gx-DiMan (x = 5, 13, and 27 nm) were found to be ~5.8, ~1.0, and ~0.2 nM for DC-SIGN, and ~14.9, ~2.7, and ~0.54 nM for DC-SIGNR, respectively, suggesting that a larger GNP scaffold provided a more favourable glycan display to enhance DC-SIGN/R binding. This is likely due to the lower surface curvature of larger GNP scaffolds which improves their surface glycan access to DC-SIGN/R CRDs for multivalent binding. (3)