Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV.
Broadly neutralizing monoclonal antibodies (bnmAbs) that target the high-mannose patch centered around the glycan at position 332 on HIV Env are promising vaccine leads and therapeutic candidates because they effectively protect against mucosal SHIV challenge and strongly suppress SHIV viremia in established infection in macaque models. However, these antibodies demonstrate varying degrees of dependency on the N332 glycan site, and the origins of their neutralization breadth are not always obvious. By measuring neutralization on an extended range of glycan site viral variants, we found that some bnmAbs can use alternate N-linked glycans in the absence of the N332 glycan site and therefore neutralize a substantial number of viruses lacking the site. Furthermore, many of the antibodies can neutralize viruses in which the N332 glycan site is shifted to the 334 position. Finally, we found that a combination of three antibody families that target the high-mannose patch can lead to 99% neutralization coverage of a large panel of viruses containing the N332/N334 glycan site and up to 66% coverage for viruses that lack the N332/N334 glycan site. The results indicate that a diverse response against the high-mannose patch may provide near-equivalent coverage as a combination of bnmAbs targeting multiple epitopes. Additionally, the ability of some bnmAbs to use other N-linked glycan sites can help counter neutralization escape mediated by shifting of glycosylation sites. Overall, this work highlights the importance of promiscuous glycan binding properties in bnmAbs to the high-mannose patch for optimal antiviral activity in either protective or therapeutic modalities.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Devin
D
Sok
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK. burton@scripps.edu katie.doores@kcl.ac.uk.
Katie J
KJ
Doores
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Bryan
B
Briney
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Khoa M
KM
Le
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Karen L
KL
Saye-Francisco
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA.
Alejandra
A
Ramos
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA.
Daniel W
DW
Kulp
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Jean-Philippe
JP
Julien
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA.
Sergey
S
Menis
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA.
Lalinda
L
Wickramasinghe
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Michael S
MS
Seaman
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02142, USA.
William R
WR
Schief
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Ian A
IA
Wilson
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, New York, NY 10038, USA.
Pascal
P
Poignard
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. 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. burton@scripps.edu katie.doores@kcl.ac.uk.
Dennis R
DR
Burton
D000911:Antibodies, Monoclonal / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000737:chemistry*; D001665:Binding Sites; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D006031:Glycosylation; D015483:HIV Antibodies / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006679:HIV Seropositivity; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008358:Mannose / Q000737:chemistry; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011134:Polysaccharides / Q000737:chemistry*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D011134:Polysaccharides; D008358:Mannose