Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

doi:10.1016/j.cell.2015.05.007

. 2015 Jun 4;161(6):1280-92.

doi: 10.1016/j.cell.2015.05.007. Epub 2015 May 21.

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Tongqing Zhou¹, Rebecca M Lynch¹, Lei Chen¹, Priyamvada Acharya¹, Xueling Wu¹, Nicole A Doria-Rose¹, M Gordon Joyce¹, Daniel Lingwood¹, Cinque Soto¹, Robert T Bailer¹, Michael J Ernandes¹, Rui Kong¹, Nancy S Longo¹, Mark K Louder¹, Krisha McKee¹, Sijy O'Dell¹, Stephen D Schmidt¹, Lillian Tran¹, Zhongjia Yang¹, Aliaksandr Druz¹, Timothy S Luongo¹, Stephanie Moquin¹, Sanjay Srivatsan¹, Yongping Yang¹, Baoshan Zhang¹, Anqi Zheng¹, Marie Pancera¹, Tatsiana Kirys¹, Ivelin S Georgiev¹, Tatyana Gindin², Hung-Pin Peng³, An-Suei Yang³; NISC Comparative Sequencing Program; James C Mullikin⁴, Matthew D Gray⁵, Leonidas Stamatatos⁵, Dennis R Burton⁶, Wayne C Koff⁷, Myron S Cohen⁸, Barton F Haynes⁹, Joseph P Casazza¹, Mark Connors¹⁰, Davide Corti¹¹, Antonio Lanzavecchia¹², Quentin J Sattentau¹³, Robin A Weiss¹⁴, Anthony P West Jr¹⁵, Pamela J Bjorkman¹⁶, Johannes F Scheid¹⁷, Michel C Nussenzweig¹⁸, Lawrence Shapiro¹⁹, John R Mascola²⁰, Peter D Kwong²¹

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
³ Genomics Research Center, Academia Sinica, and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 11221.
⁴ NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA.
⁷ International AIDS Vaccine Initiative, New York, NY 10038, USA.
⁸ Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics, and Immunology, Duke University School of Medicine and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, NC 27710, USA.
¹⁰ HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland; Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
¹² Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
¹³ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, UK.
¹⁴ Division of Infection & Immunity, University College London, Gower Street, London WC1E 6BT, UK.
¹⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁶ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁷ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
¹⁸ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
¹⁹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
²⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
²¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.

PMID: 26004070
PMCID: PMC4683157
DOI: 10.1016/j.cell.2015.05.007

Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

Tongqing Zhou et al. Cell. 2015.

. 2015 Jun 4;161(6):1280-92.

doi: 10.1016/j.cell.2015.05.007. Epub 2015 May 21.

Authors

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
³ Genomics Research Center, Academia Sinica, and Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 11221.
⁴ NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA.
⁷ International AIDS Vaccine Initiative, New York, NY 10038, USA.
⁸ Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics, and Immunology, Duke University School of Medicine and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, NC 27710, USA.
¹⁰ HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland; Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
¹² Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
¹³ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, UK.
¹⁴ Division of Infection & Immunity, University College London, Gower Street, London WC1E 6BT, UK.
¹⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁶ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
¹⁷ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
¹⁸ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
¹⁹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry & Molecular Biophysics and Department of Systems Biology, Columbia University, New York, NY 10032, USA.
²⁰ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
²¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov.

PMID: 26004070
PMCID: PMC4683157
DOI: 10.1016/j.cell.2015.05.007

Abstract

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.

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Figures

**Figure 1. Crystal Structures of Eight CD4bs Antibodies in Complex with HIV-1 gp120 Show Similar Heavy and Light Chain Orientations**
Complex structures are shown from a common alignment with gp120 (gray surface representation), with the light chain shown in blue and the heavy chains shown in red, green, and brown for CDR H3-dominated recognizers, VH1-2-derived heavy chains, and VH1-46-derived heavy chains, respectively. See also Figure S1, Table S1 and S2.

**Figure 2. Broadly Neutralizing CD4bs Antibodies Fall into Two Types: CDR H3- Dominated and V_H-Gene-Restricted (VH1-2 or VH1-46)**
(A) Percent of surface area buried in the gp120 interface for each CDR of heavy chain (left) and light chain (right). (B) Orientation of heavy-chain component of CD4bs antibody on gp120 relative to CD4. Structures determined here are shown as solid squares. Notably, newly determined structures - 8ANC131, VRC13, VRC16, and HJ16 - have orientations that differ from the previously published VRC01-class and CH103 antibodies. (C) Angles of approach for CD4bs antibodies on the trimer spike in its pre-fusion near-native conformation. Left, the HIV-1 Env trimer is shown as a gray surface with N-linked glycans in teal stick representation. The CD4-binding site on the outer domain of gp120 is represented as a yellow surface; the binding orientation of CD4 (domains 1 and 2) is shown with a yellow line; the binding orientations of CD4bs antibodies are shown with a red line for CDR H3-dominated, green for VH1-2-gene-restricted, and brown for VH1-46-gene-restricted. Right, histogram of explicit angles of approach are provided in the trimer coordinate system shown at left in which a latitudinal angle of 0 coincides with the trimer 3-fold axis. (D) Binding orientation for CDR H3-dominated and VH-gene-restricted CD4bs antibodies. The light chains of antibodies are colored in slate blue and the heavy chains are colored red for CDR H3-dominated antibodies, dark green for VH1-2-gene restricted antibodies, and brown for VH1-46-restricted antibodies. See also Figure S2 and S3, Table S3 and S4.

**Figure 3. Neutralization Breadth of CD4bs Antibodies Correlates with Angular Difference from the Most Effective Antibodies**
Correlation between antibody breadth and the angular difference of the heavy chain relative to the most effective antibodies. Upper panel, all CD4bs antibodies relative to the most effective antibody, VRC07-523; Middle panel, CDR H3-dominated antibodies relative to the most effective CDR H3-dominated antibody, VRC13; Lower panel, VH-gene-restricted antibodies relative to the most effective V_H-gene-restricted antibody, VRC07-523. For clarity, antibodies are only labeled in the middle and lower panels. To determine a common reference frame for calculations of angular difference, antibody-gp120 structures were first aligned to a common reference frame based on core gp120; to determine angular difference relative to the most effective antibody, a second superposition was performed to align each antibody to the most effective antibody referent; rotation angles determined from this second superposition are shown.

**Figure 4. Characteristics of B Cell Ontogenies for Effective CD4bs Antibodies**
(A) Affinities for germline reverted (gHgL) and mature antibodies to six diverse gp120s. Clade of each isolate is shown in parentheses after the strain name. (B) Similarities in heavy chain maturation. Numbers in the table correspond to the number of heavy chain sequences retrieved from heavy chain transcripts determined by NGS of B cells from each donor; retrieval was accomplished by cross-donor phylogenetic analysis with the template antibody from the first column. Gray highlighted areas correspond to matching lineages and classes. The table diagonal represents matching antibodies and donors; when antibodies are found off the diagonal, this indicates similarity in heavy chain maturation. (C) Class characteristics of effective CD4bs antibodies. See also Figure S4 and Table S5.

**Figure 5. The CD4 Supersite**
(A) Antibodies from 14 donors define an immunological supersite of HIV-1 vulnerability. A composite of the breadth-coded epitope surfaces shown in (B) are mapped to the gp120 surface. The yellow outline defines the outer-domain contact of the CD4 receptor. (B) Epitopes of CD4bs antibodies colored by breadth. (C) Dendrogram constructed from similarities in neutralization fingerprint based on serologic analysis with a 178 virus panel; insert shows the HIV-1 viral spike, with membrane at top, with major epitopes labeled; epitope colors correspond to antibody colors in the dendrogram. (D) Potency of CD4-binding site antibodies mapped to the supersite. The worm representation of HIV-1 gp120 is colored by averaged antibody potency with thickness representing average buried binding surface area of corresponding residues; notably, in addition to the outer domain contact on gp120 for CD4, neighboring regions in the inner domain and on strands β20/21 contribute to the supersite. See also Figure S5.

**Figure 6. Paratopes of Effective CD4bs Antibodies Are Extremely Diverse**
Recognition hotspots of CD4bs antibodies and CD4 are shown with antibodies labeled by class (top line) and representative member (bottom line). (A) CD4bs recognition of Phe43 cavity. Antibody or CD4 are shown in ribbon representation, with the side chain closest to the Phe43 cavity shown in stick representation; gp120 is shown as a gray surface. (B) CD4bs recognition of Asp368 on gp120. Coloring is the same as in (A), but gp120 is shown in ribbon representation, with the Asp368 side chain in stick representation. See also Figure S6 and Table S6.

**Figure 7. Chemistry of CD4 Supersite Recognition by Effective Neutralizing Antibodies**
(A) Chemistry of recognition surfaces is shown for each of the CD4bs antibody classes and CD4. Antibody 8ANC131 is shown for 8ANC131 class; VRC01 is shown for the VRC01 class. Insets show these representative members of each antibody class bound to the CD4 supersite on the HIV-1 Env trimer (gray surface, with N-linked glycans shown in teal stick representation). (B) Intra-class comparison of paratope atom type (top row, colored as in key for (A)) and somatic hypermutation (bottom row, with colors defined in key for (B)). See also Figure S7 and Table S7.

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[1] Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010;66:213–221. - PMC - PubMed

[2] Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010;66:213–221. - PMC - PubMed

[3] Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, Decker JM, Wycuff D, Harris L, Hawkins N, et al. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. Journal of virology. 2008;82:11651–11668. - PMC - PubMed

[4] Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, Decker JM, Wycuff D, Harris L, Hawkins N, et al. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. Journal of virology. 2008;82:11651–11668. - PMC - PubMed

[5] Braden BC, Souchon H, Eisele JL, Bentley GA, Bhat TN, Navaza J, Poljak RJ. Three-dimensional structures of the free and the antigen-complexed Fab from monoclonal anti-lysozyme antibody D44.1. Journal of molecular biology. 1994;243:767–781. - PubMed

[6] Braden BC, Souchon H, Eisele JL, Bentley GA, Bhat TN, Navaza J, Poljak RJ. Three-dimensional structures of the free and the antigen-complexed Fab from monoclonal anti-lysozyme antibody D44.1. Journal of molecular biology. 1994;243:767–781. - PubMed

[7] Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, Sawyer LS, Hendry RM, Dunlop N, Nara PL, et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994;266:1024–1027. - PubMed

[8] Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, Sawyer LS, Hendry RM, Dunlop N, Nara PL, et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994;266:1024–1027. - PubMed

[9] Calarese DA, Scanlan CN, Zwick MB, Deechongkit S, Mimura Y, Kunert R, Zhu P, Wormald MR, Stanfield RL, Roux KH, et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science. 2003;300:2065–2071. - PubMed

[10] Calarese DA, Scanlan CN, Zwick MB, Deechongkit S, Mimura Y, Kunert R, Zhu P, Wormald MR, Stanfield RL, Roux KH, et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science. 2003;300:2065–2071. - PubMed

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Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

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Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

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