Poster Sessions

SB -18

Young Do Kwon

Y. D. Kwon, L. Chen, M. Tang, M. Posner, R. Wyatt, P. Kwong

Between Scylla and Charybdis: Insights into HIV-1 neutralization from the structure of the F105 antibody in complex with gp120

Entry of human immunodeficiency virus type 1 (HIV-1) is initiated by binding of the HIV-1 gp120 envelope glycoprotein to the CD4 receptor on host cells. On gp120, the binding site for CD4 is both conserved and exposed and thus forms a potential epitope for antibody-mediated neutralization. Indeed, part of this site – the initial site of CD4 contact – is a site of vulnerability that rare antibodies like b12 can recognize to broadly neutralize HIV-1. Virtually all antibodies reactive with the CD4-binding site (CD4BS), however, are non-potent and neutralize only laboratory-adapted strains of HIV-1, not primary isolates. To understand the mechanism for how HIV-1 evades neutralization from most CD4BS antibodies, we solved the crystal structure of HIV-1 gp120 in complex with F105, a prototypic non-neutralizing CD4BS antibody. The structure reveals that the overall conformation of F105-bound gp120 is similar to its CD4-bound conformation. However, one important region, the “bridging sheet” is strikingly different. The bridging sheet is a four-stranded sheet that assembles upon CD4 binding and forms part of the CD4-interactive surface. In the F105-bound conformation, the two ß-hairpins that form the bridging sheet shift location dramatically, with select elements moving over 50 Å. This movement exposes a conserved hydrophobic surface, which is recognized by the third heavy chain complementary-determining region (CDR H3) of F105. Modeling of the F105-bound conformation of gp120 into its expected orientation in the oligomeric viral spike indicates that the bridging sheet displacement is incompatible with the more rigid viral spikes found on primary HIV-1 isolates. Tethering the bridging sheet in place to cover the hydrophobic surface recognized by F105 created a mutant gp120 recognized by CD4 and b12, but not by a panel of the non-potent CD4BS antibodies that are usually elicited. The bridging sheet movement and uncovered hydrophobic surface thus constitute a decoy mechanism that elicits antibodies unable to bind to the viral spike on primary isolates. The b12-related site of vulnerability is sandwiched between this newly revealed hydrophobic surface (akin to Charybdis) and the protruding glycan shield (akin to Scylla). Successful neutralization of HIV-1 at the site of CD4-binding appears to involve bull’s eye targeting between protruding Scylla and hydrophobic Charybdis to the initial site of CD4 attachment on gp120.