title: Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens.
abstract: A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037; Program in Molecular Structure and Function, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada; Departments of Biochemistry and Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada; wilson@scripps.edu jean-philippe.julien@sickkids.ca abward@scripps.edu.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ozorowski
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Yuanzi
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Alba
authors.initials: A
authors.lastname: Torrents de la Peña
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Steven W
authors.initials: SW
authors.lastname: de Taeye
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Travis
authors.initials: T
authors.lastname: Nieusma
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: Albert
authors.initials: A
authors.lastname: Cupo
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: Anila
authors.initials: A
authors.lastname: Yasmeen
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: Michael
authors.initials: M
authors.lastname: Golabek
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: Pavel
authors.initials: P
authors.lastname: Pugach
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: P J
authors.initials: PJ
authors.lastname: Klasse
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037; wilson@scripps.edu jean-philippe.julien@sickkids.ca abward@scripps.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.affiliation: Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative ( IAVI) Neutralizing Antibody Center, Collaboration for AIDS Vaccine Discovery, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037 wilson@scripps.edu jean-philippe.julien@sickkids.ca abward@scripps.edu.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D020285:Cryoelectron Microscopy; D015195:Drug Design; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008958:Models, Molecular; D016624:Negative Staining; D055503:Protein Multimerization; D055550:Protein Stability; D012995:Solubility; D013696:Temperature; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000276:immunology*
chemical_list: D015488:HIV Antigens; D007140:Immunoglobulin Fab Fragments; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: HIV immunogens; HIV-1 envelope; antigenic diversity; clade C trimers; neutralizing antibodies