A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies
By R. Sanders, R. Derking, A. Cupo, J. Julien, A. Yasmeen, N. Val, Helen J. Kim, C. Blattner, A. T. D. L. Peña, Jacob Korzun and 9 more. PLoS Pathogens, 2013
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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.
Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging, Virology
View Paper: https://www.semanticscholar.org/paper/77c05ebac2bdea3069ae902dbfdda5ce76aac7ff
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Citations in the corpus
- Crystal structure of a soluble cleaved HIV-1 envelope trimer (2013, methodology): “The crystal structure of the soluble BG505 SOSIP.664 trimer is in excellent agreement (fig.”
- Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens (2020, methodology): “We sought to develop a general computational method for de novo designing protein nanoparticles with geometries tailored to present antigens of interest, focusing specifically on the prefusion conformations of the trimeric viral glycoproteins HIV-1 Env (BG505 SOSIP) (Wang et al., 2017; Sanders et al”
- Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles (2016, positive): “The BG505 SOSIP.664 gp140 trimer 6 has provided an excellent antigenic 7,8 and structural 9–11 mimic of the native spike.”
- Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization (2018, neutral): “664 N241 N289 Produced in house (Sanders et al., 2013) N/A”
- Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability (2016, positive): “Previously, 19b was found to bind the SOSIP trimer by enzyme-linked immunosorbent assay (ELISA), but only to a limited extent by EM and surface plasmon resonance (SPR) 11,12 .”
- HIV-1 envelope trimer fusion proteins and their applications (2016, neutral): “5 μg/ml), essentially as described before [2, 9].”