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TitleNeutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles.
Journal, issue, pagesmBio, Vol. 12, Issue 3, Page e0042921, Year 2021
Publish dateJun 29, 2021
AuthorsSonu Kumar / Xiaohe Lin / Timothy Ngo / Benjamin Shapero / Cindy Sou / Joel D Allen / Jeffrey Copps / Lei Zhang / Gabriel Ozorowski / Linling He / Max Crispin / Andrew B Ward / Ian A Wilson / Jiang Zhu /
PubMed AbstractThe immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and ...The immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and repertoire sequencing to identify neutralizing antibodies (NAbs) from immunized animals. A panel of mouse NAbs was isolated from mice immunized with a 60-meric I3-01 NP presenting 20 stabilized trimers. Three mouse NAbs potently neutralized BG505.T332N by recognizing a glycan epitope centered in the C3/V4 region on BG505 Env, as revealed by electron microscopy (EM), X-ray crystallography, and epitope mapping. A set of rabbit NAbs was isolated from rabbits immunized with a soluble trimer and a 24-meric ferritin NP presenting 8 trimers. Neutralization assays against BG505.T332N variants confirmed that potent rabbit NAbs targeted previously described glycan holes on BG505 Env and accounted for a significant portion of the autologous NAb response in both the trimer and ferritin NP groups. Last, we examined NAb responses that were induced by non-BG505 Env immunogens. We determined a 3.4-Å-resolution crystal structure for the clade C transmitted/founder (T/F) Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend in gp41. This clade C Env, in a soluble trimer form and in a multivalent form with 8 trimers attached to ferritin NP, and the gp41-stabilized clade A Q482-d12 Env trimer elicited distinct NAb responses in rabbits, with notable differences in neutralization breadth. Although eliciting a broad NAb response remains a major challenge, our study provides valuable information on an HIV-1 vaccine design strategy that combines gp41 stabilization and NP display. Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env. This study validates the gp41 stabilization strategy for HIV-1 Env vaccine design and highlights the challenge in eliciting a broad NAb response.
External linksmBio / PubMed:34156262 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.5 - 25.0 Å
Structure data

EMDB-22999:
Negative stain reconstruction of murine antibody M4H2K1 Fab in complex with HIV-1 Env BG505 UFO.664 trimer
Method: EM (single particle) / Resolution: 25.0 Å

PDB-7kkz:
Crystal structure of mouse anti-HIV potent neutralizing antibody M4H2K1
Method: X-RAY DIFFRACTION / Resolution: 1.5 Å

PDB-7klc:
Crystal structure of M4H2K1 Fab bound to HIV-1 BG505 gp120 core and to 17b Fab
Method: X-RAY DIFFRACTION / Resolution: 4.3 Å

PDB-7kmd:
Crystal structure of a HIV-1 clade C isolate Du172.17 HR1.R4.664 Env trimer in complex with human Fabs PGT124 and 35O22
Method: X-RAY DIFFRACTION / Resolution: 3.39228580771 Å

Chemicals

ChemComp-NHE:
2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / pH buffer*YM

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-HOH:
WATER

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
  • human immunodeficiency virus 1
KeywordsANTIVIRAL PROTEIN / HIV-1 / ENV / MONOCLONAL ANTIBODY / IMMUNE SYSTEM / VIRAL PROTEIN/IMMUNE SYSTEM / mouse antibody / anti-HIV1 neutralizing antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex / HIV / envelope / glycoprotein / prefusion trimer / glycan / HIV-1 GP120 / HIV-1 GP41 / neutralizing antibodies

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