The HIV-1 envelope contains multiply overlapping (and redundant) mechanisms of humoral immune defence. These including glycan shielding, conformational masking, and immunodominant decoys with variable loops. Although explored extensively, many of these mechanisms are still only partially understood. We are using structure-based methods to define them further. In particular, we have investigated how the CD4-binding-site uses conformational masking to hide the conserved site of CD4 binding from most CD4-binding-site-directed antibodies. A portion of the CD4-binding site, however, appears to remain exposed to fulfill an unexpected viral requirement for a rapid CD4 on-rate. We initially presumed that this exposed site related solely to the site of b12 binding, on the alpha-5 helix and outer domain of gp120. However, recent analysis of the a critical part of the CD4 binding site, the interfacial Phe-43 cavity, suggests that part of this site may also be involved in initial attachment.
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