Our current observations include the lack of activity for the monovalent lectin MVN and the significantly reduced activity of the largely monomeric CV-N [P51G] mutant versus the wild-type CV-N. In contrast, HIV-1 has been shown to be as or more sensitive to CV-N [P51G] (IC 50 = 0.7-4.0 nM) than WT CV-N (IC 50 = 0.9-16 nM), suggesting that while similarities in HIV-1 and SARS-CoV-2 spike protein glycans exist, they also diverge in key aspects of their structures, relative distances between glycan sites, and importance to viral entry . Moreover, while CV-N [P51G] retains two glycan binding sites, MVN only has one, but still inhibits HIV-1 infection significantly (IC 50 =180 nM) . The fact that each CV-N monomer has two glycan binding sites likely explains why the [P51G] mutant has more potent activity against SARS-CoV-2 pseudoviruses, though still less than WT CV-N which has a significant percentage in the form of a 4-binding site CV-N dimer. Consistent with the importance of multivalency for lectin antiviral functions, SPR binding analysis of lectin-S1 interactions done as part of this study showed good fits of sensorgrams with multivalent binding models (Supplemental Figure ). As described above, multiple Spike glycans are used to enable inhibition of infection and irreversible inactivation. While the precise combinations of glycans used by the lectins for antiviral function is not defined in our current work, nor the structural ramifications of the glycosylation attachment site mutations, the preponderance of data reported here, together with previously published work on other enveloped viruses, clearly supports the important role of multivalent interactions for lectin antiviral activity. Thus, it may be speculated that virus inactivating lectins may bind to various relatively unstable conformational states of the Spike with more closely spaced glycans, pulling the equilibrium to these states and leading to irreversible alterations in the Spike. This conjecture will need future testing by determining the three-dimensional structure of lectin-Spike complexes.