Allosteric Modulation of the HIV-1 gp120-gp41 Association Site by Adjacent gp120 Variable Region 1 (V1) N-Glycans Linked to Neutralization Sensitivity
Figure 8
A, Homology model of oligomannose-glycosylated AD8 V1V2 based on the crystal structure of CAP45 V1V2 [7]. The V1V2 model, generated using the Modeller algorithm [113] within Discovery Studio 3.0, was glycosylated in silico with oligomannose side chains using the glycosciences.de server (http://www.glycosciences.de/modeling/glyprot/php/main.php) [114], [115]. The β2–β3 hairpin that forms the V1V2 base is colored green, V1 in yellow, V2 in orange. PNGSs (Asn residues shown in CPK) and oligomannose side chains are colored according to the V1V2 subdomain to which they are attached. B, Model of oligomannose-glycosylated gp120 monomer. The model, prepared with the UCSF Chimera package [117], is based on the crystal structures of the complex formed between HXBc2 gp120 with gp41-interactive region (gp120 residues 31–284, 334–501), sCD4 and 48 d Fab (PDB ID 3JWD) and the YU2 gp120 (residues 285–333)-418d Fab-sCD4 complex (PDB ID 2QAD) [5], [8]. Oligomannose addition was performed in silico as for A. The gp41 association site formed by the N- and C-terminal segments is colored green, the 7 stranded β-sandwich in purple, layer 2 and the V1V2 β2–β3 hairpin base in green, layer 1 in pink, the outer domain in red. Asn residues representing PNGSs are shown in CPK. Oligomannose glycans implicated in 2G12 recognition are colored crimson. The homology models were drawn using Pymol. C, Alignment of V1V2 amino acid sequences. Selected V1V2 sequences were initially aligned using clustalx and then adjusted manually. PNGSs are highlighted in green. Residue numbering is according to HXB2. sens: neutralization-sensitive; res: neutralization-resistant. a, Neutralization susceptibility of Envs derived from subtype B HIV-1 reference strains as determined using macaque antisera raised to SF162 gp140 immunogen [36]; b, Neutralization susceptibility phenotype associated with primary (M1) and chronic (M47, M46, M32 and M31) phase subtype A V1V2 sequences as determined with autologous plasma [42]; c, Consensus V1V2 sequences derived from neutralization-sensitive (VP-1CON) and neutralization-resistant (VP-2CON) isolates obtained from a patient with cross-reactive neutralizing activity as determined with autologous plasma [44].