HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage

Elise Landais; Ben Murrell; Bryan Briney; Sasha Murrell; Kimmo Rantalainen; Zachary T Berndsen; Alejandra Ramos; Lalinda Wickramasinghe; Melissa Laird Smith; Kemal Eren; Natalia de Val; Mengyu Wu; Audrey Cappelletti; Jeffrey Umotoy; Yolanda Lie; Terri Wrin; Paul Algate; Po-Ying Chan-Hui; Etienne Karita; IAVI Protocol C Investigators; IAVI African HIV Research Network; Andrew B Ward; Ian A Wilson; Dennis R Burton; Davey Smith; Sergei L Kosakovsky Pond; Pascal Poignard

doi:10.1016/j.immuni.2017.11.002

HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage

Immunity. 2017 Nov 21;47(5):990-1003.e9. doi: 10.1016/j.immuni.2017.11.002.

Authors

Elise Landais¹, Ben Murrell², Bryan Briney³, Sasha Murrell⁴, Kimmo Rantalainen⁴, Zachary T Berndsen⁴, Alejandra Ramos⁵, Lalinda Wickramasinghe⁵, Melissa Laird Smith⁶, Kemal Eren⁷, Natalia de Val⁸, Mengyu Wu⁹, Audrey Cappelletti¹⁰, Jeffrey Umotoy⁵, Yolanda Lie¹¹, Terri Wrin¹¹, Paul Algate¹², Po-Ying Chan-Hui¹², Etienne Karita¹³; IAVI Protocol C Investigators; IAVI African HIV Research Network; Andrew B Ward⁸, Ian A Wilson¹⁴, Dennis R Burton¹⁵, Davey Smith¹⁶, Sergei L Kosakovsky Pond², Pascal Poignard¹⁷

Affiliations

¹ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA. Electronic address: elandais@iavi.org.
² Department of Medicine, University of California San Diego, San Diego, CA 92103, USA.
³ Department of Immunology and Microbiology, 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.
⁴ Department of Integrative Structural and Computational Biology, 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.
⁵ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA.
⁶ Icahn School of Medicine and Icahn Institute for Genomics and Multiscale Biology at Mount Sinai, New York, NY 10029, USA.
⁷ Biomedical Informatics, University of California San Diego, San Diego, CA 92103, USA; Bioinformatics and Systems Biology, University of California San Diego, San Diego, CA 92103, USA.
⁸ International AIDS Vaccine Initiative Neutralizing Antibody Center, 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; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁰ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Institut de Biologie Structurale, Université Grenoble Alpes, Commissariat a l'Energie Atomique, Centre National de Recherche Scientifique and Centre Hospitalier Universitaire Grenoble Alpes, 38044 Grenoble, France.
¹¹ Monogram Biosciences Inc., Laboratory Corporation of America Holdings, San Francisco CA 94080, USA.
¹² Theraclone Sciences, Inc., Seattle, WA 98104, USA.
¹³ Rwanda-Zambia HIV Research Group, Project San Francisco, Kigali, Rwanda.
¹⁴ International AIDS Vaccine Initiative Neutralizing Antibody Center, 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; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁵ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, 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, Cambridge, MA 02114, USA.
¹⁶ Department of Medicine, University of California San Diego, San Diego, CA 92103, USA; Veterans Affairs Healthcare System, San Diego, CA 92161, USA.
¹⁷ International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA; Institut de Biologie Structurale, Université Grenoble Alpes, Commissariat a l'Energie Atomique, Centre National de Recherche Scientifique and Centre Hospitalier Universitaire Grenoble Alpes, 38044 Grenoble, France. Electronic address: pascal.poignard@ibs.fr.

Abstract

Understanding how broadly neutralizing antibodies (bnAbs) to HIV envelope (Env) develop during natural infection can help guide the rational design of an HIV vaccine. Here, we described a bnAb lineage targeting the Env V2 apex and the Ab-Env co-evolution that led to development of neutralization breadth. The lineage Abs bore an anionic heavy chain complementarity-determining region 3 (CDRH3) of 25 amino acids, among the shortest known for this class of Abs, and achieved breadth with only 10% nucleotide somatic hypermutation and no insertions or deletions. The data suggested a role for Env glycoform heterogeneity in the activation of the lineage germline B cell. Finally, we showed that localized diversity at key V2 epitope residues drove bnAb maturation toward breadth, mirroring the Env evolution pattern described for another donor who developed V2-apex targeting bnAbs. Overall, these findings suggest potential strategies for vaccine approaches based on germline-targeting and serial immunogen design.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

AIDS Vaccines / immunology
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / physiology*
Cell Lineage*
Complementarity Determining Regions
HIV Antibodies / chemistry
HIV Antibodies / physiology*
Humans
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

AIDS Vaccines
Antibodies, Neutralizing
Complementarity Determining Regions
HIV Antibodies
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding