Crystal structure of the neutralizing antibody HK20 in complex with its gp41 antigen
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1 Crystal structure of the neutralizing antibody HK20 in complex with its gp41 antigen David Lutje Hulsik Unit for Virus Host Cell Interaction UMI 3265 University Joseph Fourier-EMBL-CNRS, Grenoble
2 Env catalyzed fusion reaction gp41 intermediate fusion conformation: HR1 and HR2 are transiently exposed -target for antibodies such as HK-20 Limited time span, HR1 epitopes only present during fusion [Corti et al. PLoS One. 2010; 5(1): e8805]
3 Mapping of human MAb HK20 HK20: 562 QQHLLQLTVWGIKQL 576 [Corti et al. PLoS One. 2010; 5(1): e8805]
4 HK20 shows broad neutralization Neutralization of 20 HIV-1 isolates in HOS assay. HK20 as broad as 4E10 [Corti et al. PLoS One. 2010; 5(1): e8805]
5 HK20 footprint targeted by antibodies in HIV patients HK20 like antibodies are produced during infection. 20 HIV-infected patient sera out of 33 compete with HK20. HK20 epitope is immunogenic Davide Corti and Antonio Lanzavecchia, IRB
6 5-Helix gp41 mimetic to study the HK20 interaction gp41 5HB
7 Crystal structure of gp41 in complex with Fab HK20 C L V L d b HR 2 a HR 1 Resolution 2.3 Å R = 23.0 % R free = 28.0 % 90 C H V H V L a c HR 1 b c e C L V H C H d e HR 2
8 HK20 can occupy 3 binding sites on gp41 Virus membrane 90 fp Cell membrane Docking of HK20 on trimer
9 Close-up of gp41-hk20 interaction Key determinants CDR H2, H3, L3 Contacts: 2 HR1 helices
10 mab D5 targets the same HR1 epitope C alpha overlay of HK20-5Helix and D5-5Helix reveal differences in the approach angle: HK20 binds in a 60 angle to trimer axis D5 binds 90 angle to axis of HR1 trimer C alpha overlay of HK20-Fab and D5-Fab confirm differences relative to the gp41 orientation [D5 structure: Luftig et al. NSMB, 2006]
11 HK20 and D5 target the same epitope: Buried surfaces HK20 D5 R 579 Q577 K 574 Q 575 Q 577 K 574 I 573 Q 567 N 636 L 568 K 574 Q 567 W 571 W 571 Q 563 H 564 H H Q 575 I 573 K574 K D = 3.3 nm HR1 only CDR H2, H3, L3 K D = 3.1 nm HR1 + HR2 All CDRs
12 HK20 and D5 mimic the HR2 recognition of the HR1 hydrophobic pocket gp41 D5 HK20 W570 W626 W631 I635 W570 F54 W570 F54 H564 H564 H564 F54 Inhibiting HR2 HR1 No fusion possible
13 HK20 shows higher potency and breadth of neutralization compared to D5 TZM-b1 HK20: 4 out of 18 HIV-1 isolates D5: 1 out of 18 HOS HK20: all 18 D5: 11 out of 18 Davide Corti & Antonio Lanzavecchia, IRB Mike Seaman, Harvard 13
14 Size dependent neutralization activity of HK20 27 B isolates 25 C isolates IgG 150 kda Fab 50 kda scfv 25 kda 45 HIV-1 pseudoviruses HK20 shows greater potency for clade C viruses compared to clade B Davide Corti & Antonio Lanzavecchia, IRB Mike Seaman, Harvard
15 HK20 scfv reveals similar breadth but lower potency in comparison to T-20 Similar mode of interaction Different interaction site 20 isolates
16 HK20 scfv are active in a PBMC neutralization assay PBMC-assay: 8 of 9 isolates neutralized by HK20 scfv Lara Mainetti, Gabriella Scarlatti; San Raffaele Scientific Institute, Milan
17 Summary HK20 interacts with high affinity with a conserved hydrophobic epitope on gp41 (HR1). HK20 employs mainly heavy chain CDR H2 and H3 for epitope recognition. (binding site generated via 13 somatic mutations) 3 antibodies could target the HR1 trimer at the same time. HK20 epitope antibodies are produced in HIV-infected patients; immunogenic HK20 IgG shows a broad neutralization breadth compared to D5 IgG HR1 seems sterically occluded since HK20 Fab and scfv show higher breadth and potency then HK20 IgG Difference in approach angle of HK20 compared to D5 might explain it s broader breadth in neutralization Not only steric occlusion of the epitope but also temporal limitation of the HR1 epitope accessibility / HK20 works better in HOS compared to TZM-b1
18 Acknowledgements Charles Sabin, Victor Buzon, Andreas Hinz, Winfried Weissenhorn; UVHCI, Grenoble Davide Corti, Chiara Silacci, Frederica Sallusto, Antonio Lanzaveccia; Institute for Research in Biomedicine, Bellinzona Fabrizia Vanzetta, Gloria Agatic; Humabs SAGL, Bellinzona Mike S. Seaman; Beth Israel Deaconess Medical Center, Boston Lara Mainetti, Gabriella Scarlatti; San Raffaele Scientific Institute, Milan Robin Weiss, University College, London
19 David Lutje Hulsik 1, Charles Sabin 1, Davide Corti 2, Victor Buzon 1, Hans Langedijk 3, Antonio Lanzavecchia 2 and Winfried Weissenhorn 1 1 Unit of Virus Host Cell Interactions (UVHCI) UMI 3265 Université Joseph Fourier-EMBL-CNRS, Grenoble, France 2 Institute for Research in biomedicine, Bellinzona, Switzerland 3 Pepscan Therapeutics B.V. Lelystad, The Netherlands Introduction: The monoclonal gp41-specific antibody HK20 was isolated from human memory B cells. The epitope was mapped to the triple stranded coiled-coil region formed by HR-1 of gp41. HK20 is broadly neutralizing, particularly as a Fab fragment but reveals strong assay-dependent selectivity in its neutralization activity. Materials and Methods: In order to understand the structural basis of HK20 reactivity we have solved the crystal structure of a Fab fragment in complex with the 5-helix bundle construct of gp41. We used SPR measurements to determine the KD of both antibodies and Fabs of HK20 as well as D5, an antibody with similar HR-1 specific reactivity. Results: The structure was refined to a resolution of 2.3 Å. HK20 utilizes its CDR H1-3 and L3 loops to contact a hydrophobic pocket formed by two adjacent HR1 helices. Molecular details show that CDR H2 residues Ile53, Phe54 and Asp 55 are ideally positioned to fill the hydrophobic pocket that is occupied by HR2 residues Trp626, Trp631 and Ile 635 in the post fusion conformation. HK20 contacts only HR1 residues in comparison to D5, which revealed also few HR2 contacts. The HK20-gp41 interaction is such that each trimer could interact with three antibodies. Although the binding affinities of HK20 and D5 are similar their angle of interaction with gp41 is slightly different. Conclusion: Although the HR1 epitope is only transiently exposed during the conformational changes that lead to fusion of viral and cellular membranes, the high conservation of this epitope renders it an attractive target for vaccine development. Our structural studies provide the atomic details of interaction and give insight into the requirements of an antigen that could induce HK20-like immune responses.
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