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Abstract
The N-terminal fusion peptide (FP) of the human immunodeficiency virus (HIV)-1 envelope glycoprotein (Env) gp41 subunit plays a critical role in cell entry. However, capturing the structural flexibility in the unbound FP is challenging in the native Env trimer. Here, FP conformational isomerism is observed in two crystal structures of a soluble clade B transmitted/founder virus B41 SOSIP.664 Env with broadly neutralizing antibodies (bNAbs) PGT124 and 35O22 to aid in crystallization and that are not specific for binding to the FP. Large rearrangements in the FP and fusion peptide proximal region occur around M530, which remains anchored in the tryptophan clasp (gp41 W623, W628, W631) in the B41 Env prefusion state. Further, we redesigned the FP at position 518 to reinstate the bNAb VRC34.01 epitope. These findings provide further structural evidence for the dynamic nature of the FP and how a bNAb epitope can be restored during vaccine design.
Highlights
The N-terminal fusion peptide (FP) of the human immunodeficiency virus (HIV)-1 envelope glycoprotein (Env) gp[41] subunit plays a critical role in cell entry
We found that B41 SOSIP.[664] trimers expressed in either HEK293S cells or HEK293F cells (Tm = 57.6 °C) cells are stable (Supplementary Figure 1A), but less so than BG505 SOSIP.66410
The B41 SOSIP.[664] trimers were further stabilized by binding to Fabs PGT124 and 35O22, which increase the melting temperatures by ~5 °C and an additional ~1.5 °C, respectively (Supplementary Fig. 1b)
Summary
The N-terminal fusion peptide (FP) of the human immunodeficiency virus (HIV)-1 envelope glycoprotein (Env) gp[41] subunit plays a critical role in cell entry. To construct a soluble, cleaved, native-like gp[140] trimer as a potential vaccine immunogen, HIV-1 Env was first stabilized with a disulfide bond between gp[120] and gp[41] and an I559P mutation in gp[41]; a more efficient cleavage site and truncation at residue 664 created the SOSIP.[664] design[7,8,9,10,11,12]. These major advances enabled determination of the x-ray and cryo-EM structures of the closed, prefusion native-like HIV-1 Env[13,14,15].
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