Broad and potent neutralization of HIV-1 by a gp41-specific human antibody

Abstract

Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ~98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site-of-vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical Arg/Lys just prior to the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 Env.

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…In a live-virus assay, the 10E8 HIVCAR T cells were also the only HIVCAR cells tested that failed to control HIV JR-CSF replication, as measured by supernatant p24. Although 10E8 has been shown to neutralize JR-CSF efficiently, 52 our finding is perhaps not surprising given the observation that anti-MPER antibodies bind poorly to the surface of infected cells. 59 The potency of different HIVCARs against different viral variants supports the pursuit of HIVCAR combinations.…”

“…51 We chose four highbreadth, high-potency bNAbs that bind different epitopes on the HIV envelope glycoprotein ( Figure 1A): PGT-145 (variable regions 1 and 2 glycan loop), VRC07-523 (CD4-binding site), PGT-128 (mannose-rich region), and 10E8 (gp41 membrane-proximal external region). [51][52][53][54] To generate anti-HIVCARs, the heavy and light chains of each bNAb were synthesized as an scFv and cloned into a lentivirus (LV) second-generation CAR expression construct; blue fluorescent protein (BFP) was co-expressed downstream of a self-cleaving peptide ( Figure 1B). An anti-CD19 scFv CAR (CD19CAR) was used as a control.…”

Identification and specificity of broadly neutralizing antibodies against HIV

“…The more recently isolated MPER bnAb 10E8 is highly potent and does not display any autoreactivity nor does it bind lipids as has been reported for other MPER Abs 87. This may be because 10E8 approaches MPER from an altered angle and uses a different binding mode to 4E10 36. Serum analysis suggested 10E8‐like specificities were not unusual, with 27% of 78 donors exhibiting this activity.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…The contact regions are shown on the crystal structure of a subtype G Env SOSIP trimer60 ( PDB : 5 FYJ ), colored according to the bNA b epitope, with different colors for overlapping contact sites of multiple bNA bs. For calculations of bNA b contact regions, crystal structures for antibodies CH 235.1268 ( PDB :5F96), PGT 12889 ( PDB : 5C7K) and 10E890 ( PDB :4G6F), and a structural model for CAP 256‐ VRC 26.0962 were used. A generous cutoff of 8.5 Å between heavy atoms of antibody and Env was used to define contacts, so as to capture the full region where Env amino acid substitutions might directly impact binding.…”

“…Env sequences from a often‐used 207 M‐group virus neutralization panel were used to calculate sequence entropy, and deletions were included in the entropy calculation. Entropy scores are mapped on the crystal structure for a subtype G Env SOSIP trimer60 ( PDB :5 FYJ ) and the MPER peptide90 ( PDB :4G6F) using the color scheme indicated, which uses blue for low entropy (high sequence conservation), yellow for intermediate entropy and red for high entropy (high sequence variation). The view of CAP 256‐ VRC 26.09 contacts is from the top as in right panel in (A).…”