Rational HIV immunogen design to target specific germline B cell receptors

TitleRational HIV immunogen design to target specific germline B cell receptors
Publication TypeJournal Article
Year of Publication2013
AuthorsJardine, J., Julien J. - P., Menis S., Ota T., Kalyuzhniy O., McGuire A., Sok D., Huang P. - S., MacPherson S., Jones M., Nieusma T., Mathison J., Baker D., Ward A. B., Burton D. R., Stamatatos L., Nemazee D., Wilson I. A., & Schief W. R.
JournalScience (New York, N.Y.)
Date Published2013 May 10
KeywordsAIDS Vaccines, Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antigens, CD4, B-Lymphocytes, Collaborative Publication, Crystallography, X-Ray, DNA Mutational Analysis, Germ Cells, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Macaca, Mice, Models, Animal, Molecular Sequence Data, Nanoparticles, Protein Engineering, Protein Structure, Tertiary, Receptors, Antigen, B-Cell

Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.



Alternate JournalScience
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