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. 2022 Aug 3;13(1):4515.
doi: 10.1038/s41467-022-32208-0.

Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

Jelle van Schooten  1 , Elinaz Farokhi  2 , Anna Schorcht  1 , Tom L G M van den Kerkhof  1 , Hongmei Gao  3 , Patricia van der Woude  1 , Judith A Burger  1 , Tim G Rijkhold Meesters  1 , Tom Bijl  1 , Riham Ghalaiyini  1 , Hannah L Turner  2 , Jessica Dorning  4 , Barbera D C van Schaik  5 , Antoine H C van Kampen  5 , Celia C Labranche  3 , Robyn L Stanfield  2 , Devin Sok  6   7   8   9 , David C Montefiori  3 , Dennis R Burton  6   7   9   10 , Michael S Seaman  4 , Gabriel Ozorowski  2   7   8 , Ian A Wilson  2   7   8   11 , Rogier W Sanders  1   12 , Andrew B Ward  2   7   8 , Marit J van Gils  13
Affiliations

Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein

Jelle van Schooten et al. Nat Commun. .

Abstract

A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Isolation and characterization of VH1-2-derived mAbs with average-length CDRL3 that target the CD4bs.
a Longitudinal serum neutralization (serum dilution that inhibits 50% of viral infectivity (ID50)) of donor H18877 against a multiclade virus panel. The geometric mean is represented as a blue line. Serum samples were obtained at 3.2, 7.5, 9.8, 12.3, 18.8, 25.0, 31.2, 34.9, 52.8 months post SC, while PBMCs were isolated at month 24.0 and 36.0 post SC as indicated by the black arrows. b Pie-chart of VH gene usage of isolated B cells from months 24 and 36 post SC (n = 222). Each gray-color coded slice represents a certain VH gene and the slice size is proportional with the amount of BCRs derived from this particular VH gene. BCRs using the VH1-2*02 gene are colored in blue. c Sequence characteristics of ACS101, ACS102 and ACS103 that use the VH1-2*02 and VL2-23*02 gene segments in their HC and LC, respectively. Somatic hypermutation (SHM) is depicted as the number of amino acid (aa) and nucleotide (nucl) mutations compared to the VH1-2*02 and VL2-23*02 germline genes. d Binding of ACS101, ACS102, ACS103, and VRC01 to AMC009 SOSIP using biolayer interferometry. e Negative stain electron microscopy 3D reconstructions of ACS101, ACS102, and ACS103 in complex with AMC009 SOSIP. Fabs were segmented, colored and are shown relative to a reference trimer for visualization and comparison. VRC01 (EMD-8269) Fab was included for comparison purposes.
Fig. 2
Fig. 2. ACS101 neutralization breadth and potency is inferior to those of IOMA and VRC01.
Breadth is indicated as the percentage of viruses that were neutralized. a Neutralization IC50 profile of ACS101, IOMA and VRC01 against a panel of (n = 119) Tier-2 viruses. Each symbol represents a unique HIV-1 isolate. Data for IOMA and VRC01 were derived from CATNAP. b Overview of neutralization by ACS101 against viruses from all tested panels (147 viruses in total). Breadth of ACS101 against viruses from different clades is shown with the geometric mean (potency) in μg/ml.
Fig. 3
Fig. 3. ACS101 heavy chain interactions with the CD4bs of AMC009 SOSIP and comparison to other VH1-2 and VH1-46-derived CD4bs bNAbs.
a Cryo-EM map and model of Fabs ACS101 and ACS124 in complex with AMC009 SOSIP (gp120; light brown, gp41; gray and N-linked glycans; green). ACS101 and ACS124 Fab HC and LC are color coded as indicated. Only the variable domains of Fabs ACS101 and ACS124 and one gp41-gp120 heterodimer are shown as ribbons and fitted into the cryo-EM map. ACS101 is framed by the N197, N234, N276 and N362 glycans, which are colored green in the right-hand panel. b Key interactions of ACS101, VH1-2-derived bNAbs IOMA (PDB:5T3Z) and VRC01 (PDB:3NGB), VH1-46-derived bNAb 8ANC131 (PDB:4RWY) and CD4 (PDB:1G9N) with HIV-1 gp120 (shown in light brown) at four sites: D368, F43 cavity, V5 loop and Loop D. All interactions are shown with the gp120 subunit that the bNAbs were complexed with: ACS101 (clade B AMC009 SOSIP), IOMA (clade A BG505 SOSIP), VRC01 (clade A/E 93TH057 gp120), 8ANC131 (clade B YU2 gp120) and CD4 (clade B YU2 gp120). The F43 cavity is shown as a molecular map generated at 3.5 Å resolution from the gp120 atomic coordinates with UCSF Chimera. Expected H-bonds and salt bridges are shown as dotted lines using a cut-off distance of 3.2 Å.
Fig. 4
Fig. 4. ACS101 light chain interactions with the CD4bs of AMC009 SOSIP and comparison to other VH1-2 and VH1-46-derived CD4bs bNAbs.
a Interaction of ACS101, IOMA (PDB:5T3Z) and VRC01 (3NGB) with the V5 loop. All interactions are shown with the gp120 subunit that the bNAbs were complexed with: ACS101 (clade B AMC009 SOSIP), IOMA (clade A BG505.664 SOSIP) and VRC01 (clade A/E 93TH057 gp120). b Comparison of the V5 loop of ACS101 and PGV04 (PBD:6VO3) bound to gp120. Both ACS101 and PGV04 are in complex with AMC009 SOSIP. The shift of the V5 loop is indicated as a dotted line measured from Cα- Cα of residue S460. c Interactions of ACS101 with the V5 loop and the N276 glycan. d Ribbon representations Fabs (only the light chain is shown) of ACS101 and other VH1-2 and VH1-46-derived CD4bs bNAbs (liganded) with the CDRL1 colored in red. ACS101 is shown as liganded and unliganded Fab. IOMA (PDB:5T3Z), VRC01 (PDB:3NGB) and 8ANC131 (PDB:4RWY) Fabs are liganded. e Binding of ACS101, ACS101iGL CDRL1 and ACS101IOMA CDRL1 to AMC009 SOSIP and AMC009 2 M 1F9 SOSIP using biolayer interferometry (BLI). The bNAb 2G12 and PBST + BSA (PBS pH 7.4 + 0.01% (w/v) BSA + 0.002% (v/v) Tween 20) were included as a loading and negative control, respectively. f Neutralization of AMC009 by ACS101, ACS101iGL CDRL1 and ACS101IOMA CDRL1. The length of the error bars is the standard deviation at each concentration (n = 2 biologically independent experiments).
Fig. 5
Fig. 5. Sequence alignment of longitudinal Envs from donor H18877 for three sites, e.g., Loop D, CD4-binding loop, and the β23-V5 loop.
Residues that are contacted by ACS101 revealed by the cryo-EM structure are highlighted in blue. The env sequence are named as followed; donor_name.month.clone, e.g. H18877.2 m.1F9 indicates the sequence 1F9 from donor H18877 at month 2 post SC. Symbol (~) indicate a deletion at that particular position.
Fig. 6
Fig. 6. Binding of ACS101, ACS102, and ACS103 to longitudinal Envs isolated from donor H18877.
Binding of ACS101, ACS102, and ACS103 to longitudinal Envs isolated from donor H18877 using biolayer interferometry. Heat map representing the maximum values of the binding curves measured by biolayer interferometry. The bNAbs 2G12, VRC01 and PGT151 were included as controls, whereas PBST + BSA (PBS pH 7.4 + 0.01% (w/v) BSA + 0.002% (v/v) Tween 20) was used as a negative control.
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References

    1. Global HIV & AIDS statistics—Fact sheet | UNAIDS. https://www.unaids.org/en/resources/fact-sheet.
    1. Sok D, Burton DR. Recent progress in broadly neutralizing antibodies to HIV. Nat. Immunol. 2018;19:1179. doi: 10.1038/s41590-018-0235-7. - DOI - PMC - PubMed
    1. McCoy, L. E. The expanding array of HIV broadly neutralizing antibodies. Retrovirology15, 70 (2018). - PMC - PubMed
    1. Hessell, A. J. et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 5, 5 (2009). - PMC - PubMed
    1. Moldt B, et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl Acad. Sci. USA. 2012;109:18921–18925. doi: 10.1073/pnas.1214785109. - DOI - PMC - PubMed

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