A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies

Abstract

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens.

Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2–V3 interaction and modulates neutralization sensitivity

“…Thus, the absence of sulfated tyrosines may be one of the reasons why the SOSIP.664 trimer, albeit reportedly in a "near-native" conformation (32), maintains some phenotypic properties of the open gp120 structure, such as reactivity with anti-V3 mAbs that do not neutralize the homologous virus, intermediate-affinity binding to monomeric sCD4, and an unfavorable ratio between the concentrations of trimer-preferring antibodies required for binding versus neutralization of the homologous virus (32).…”

Identification and specificity of broadly neutralizing antibodies against HIV

“…To counter the limitation of binding selection based on the gp120 subunit, Env on the surface of cells was used as a bait to select the bnAbs 3BC315 and 3BC176,44 which are also specific for the gp120‐gp41 trimer interface 45. Subsequently, advances in the production of soluble near‐native stabilized Env trimers46 have allowed better selection of Env‐specific B cells, excluding those which bind regions not exposed on the infectious viral spike. 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.…”

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

“…Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env) 1 have improved the elicitation of potent isolate-specific Ab responses in rabbits 2 and macaques 3 , but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes.…”