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Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11947-52. doi: 10.1073/pnas.1507793112. Epub 2015 Sep 8.

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens.

Author information

1
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.
2
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;
3
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
4
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021;
5
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;
6
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.
7
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.

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.

KEYWORDS:

HIV immunogens; HIV-1 envelope; antigenic diversity; clade C trimers; neutralizing antibodies

PMID:
26372963
PMCID:
PMC4586835
DOI:
10.1073/pnas.1507793112
[Indexed for MEDLINE]
Free PMC Article

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