Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody

Abstract

The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.

Identification and specificity of broadly neutralizing antibodies against HIV

“…Using this method, we isolated PGDM140028 from the same donor that previously yielded the PGT141–145 family of bnAbs via the B‐cell culturing approach 22. Furthermore, stabilized BG505 SOSIP.664 trimers have been used as baits to isolate two bnAbs which occupy overlapping epitopes at the gp120‐gp41 interface and also contact the fusion peptide, ACS20247 and VRC34 48. Similarly, additional apex‐specific bnAbs were recently isolated from the CAP256 donor using both the BG505 SOSIP.664 trimer and B‐cell culture 49.…”

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

“…For example, the eight amino acids at the N‐terminal of the fusion peptide of HIV‐1 Env in its closed prefusion state are not visualized in most crystal structures 32, 86, 87. However, we observed antibody VRC34 to recognize these eight residues as the primary determinant of binding 30. MD of the prefusion closed Env trimer revealed this eight amino acid region to be highly mobile with average solvent accessibilities in the MD simulations that correlated with VRC34 recognition [see Fig.…”

“…Alternatively, an identified antibody lineage may not contribute substantially to serum neutralization, which may be dominated by other, yet to be discovered, specificities. The fingerprinting analysis can therefore lead to a better understanding of the complexity of polyclonal sera and the effects different component antibodies can have on polyclonal neutralization; (iii) While the sera from many donors appear to contain antibodies that are similar to already known specificities, new epitopes continue to be discovered 27, 30, 33. When an antibody targeting a new epitope is discovered, the neutralization fingerprinting approach can be used to screen HIV‐infected sera for neutralization signals matching the new epitope, therefore both guiding efforts for identifying additional antibodies targeting this epitope, as well as providing an estimate of the overall prevalence of such antibodies in infected donors.…”

“…This new technology has resulted in the isolation of over 2000 complete V H :V L sequences of the VRC34 antibody class, which targets the fusion peptide as a new vulnerable epitope on the HIV trimer 30. V H :V L genetic lineage targeting is particularly promising for the identification of early antibody variants from longitudinal samples (both human and primate), because early antibodies may not bind to B‐cell probes with sufficient affinity for single‐cell sorting, and also may be weakly or narrowly neutralizing and therefore refractory to identification via single‐cell microneutralization.…”

“…MD of the prefusion closed Env trimer revealed this eight amino acid region to be highly mobile with average solvent accessibilities in the MD simulations that correlated with VRC34 recognition [see Fig. 4B and C 30]. …”