Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope

Abernathy, M. E.; Gristick, H. B.; Vielmetter, J.; Keeffe, J. R.; Gnanapragasam, P. N.; Lee, Y. E.; Escolano, A.; Gautam, R.; Seaman, M. S.; Martin, M. A.; Nussenzweig, M. C.; Bjorkman, P. J.

doi:10.1101/2021.03.17.435265

bioRxiv · 10.1101/2021.03.17.435265

Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope

Abernathy, M. E.·Gristick, H. B.·Vielmetter, J.·Keeffe, J. R.·Gnanapragasam, P. N.·Lee, Y. E.·Escolano, A.·Gautam, R.·Seaman, M. S.·Martin, M. A.·Nussenzweig, M. C.·Bjorkman, P. J.

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Abstract

HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. Here we report isolation and characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7[A] cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, implying that only two fusion peptides per trimer are required for viral-host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.

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Abernathy, M. E., Gristick, H. B., Vielmetter, J., Keeffe, J. R., Gnanapragasam, P. N., Lee, Y. E., Escolano, A., Gautam, R., Seaman, M. S., Martin, M. A., Nussenzweig, M. C., Bjorkman, P. J.. 2021-03-17. Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope. https://doi.org/10.1101/2021.03.17.435265

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