Background: HIV-1 envelope glycoprotein (Env), a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding to closed Env displaces the V1V2 loops from Env‘s apex, allowing co-receptor binding and opening Env to enable gp41-mediated fusion.
Methods: Using single-particle cryoEM methods, we solved the
sCD4-bound structure of a clade B B41 SOSIP trimer in complex with 21c, a CD4-induced (CD4i) coreceptor-mimicking antibody, and with 8ANC195, a broadly neutralizing antibody (bNAb) that recognizes the gp120-gp41 interface, to a resolution of 4.05 Å.
Results: Despite binding of the 8ANC195 Fab that partially closes the open, sCD4-bound Env conformation, our structure shows rearrangements in gp120, including displacement of V1V2, exposure of V3, formation of the 4-stranded bridging sheet, and formation of the α0 helix. In addition, unlike the V1V2 regions in similar sCD4-bound Env structures complexed with the CD4i antibody 17b, the displaced V1V2 loops in the B41-sCD4-21c-8ANC195 structure exhibited ordered density allowing the structure of the displaced
V1V2 to be determined for the first time. Comparing partially- and fully-open Envs with closed Envs shows that gp41 rearrangements are independent of CD4-induced gp120 bridging sheet formation and V1V2 displacement, suggesting an order of conformational changes before co-receptor binding: (i) gp120 opening inducing side chain rearrangements and a compact gp41 central helix conformation, and (ii) bridging sheet formation, and V1V2 displacement.
Conclusions: Analyses of these results further our understanding of HIV-1 Env conformational changes leading to fusion and provide templates for designing agents to disrupt HIV-1 entry into target cells
