Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

Williams, W. B.; Meyerhoff, R.; Edwards, R. J.; Li, H.; Nicely, N.; Henderson, R.; Zhou, Y.; Janowska, K.; Mansouri, K.; Manne, K.; Stalls, V.; Hsu, A. L.; Borgnia, M. J.; Stewart-Jones, G.; Lee, M. S.; Bronkema, N.; Perfect, J.; Moody, A.; Wiehe, K.; Bradley, T.; Kepler, T. B.; Alam, M.; Parks, R. J.; Foulger, A.; Bonsignori, M.; LaBranche, C. C.; Montefiori, D. C.; Seaman, M.; Santra, S.; Francica, J. R.; Lynn, G. M.; Aussedat, B.; Walkowicz, W. E.; Laga, R.; Kelsoe, G.; Saunders, K. O.; Fera, D.; Kwong, P. D.; Seder, R. A.; Bartesaghi, A.; Shaw, G. M.; Acharya, P.; Haynes, B. F.

doi:10.1101/2020.06.30.178921

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bioRxiv · 10.1101/2020.06.30.178921

Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

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Abstract

SummaryThe HIV-1 envelope (Env) is comprised by mass of over 50% glycans. A goal of HIV-1 vaccine development is the induction of Env glycan-reactive broadly neutralizing antibodies (bnAbs). The 2G12 bnAb recognizes an Env glycan cluster using a unique variable heavy (VH) domain-swapped conformation that results in fragment antigen-binding (Fab) dimerization. Here we describe Fab-dimerized glycan (FDG)-reactive antibodies without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques that neutralized heterologous HIV-1 isolates. FDG precursors were boosted by vaccination in macaques, and were present in HIV-1-naïve humans with an average estimated frequency of one per 340,000 B cells. These data demonstrate frequent HIV-1 Env glycan-reactive bnAb B cell precursors in macaques and humans and reveal a novel strategy for their induction by vaccination.HighlightsDiscovery of Fab-dimerized HIV-1 glycan-reactive antibodies with a non-domain-swapped architectureFab-dimerized antibodies neutralize heterologous HIV-1 isolates.Antibodies with this architecture can be elicited by vaccination in macaques.Fab-dimerized antibodies are found in HIV-1 naïve humans.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Williams, W. B., Meyerhoff, R., Edwards, R. J., Li, H., Nicely, N., Henderson, R., Zhou, Y., Janowska, K., Mansouri, K., Manne, K., Stalls, V., Hsu, A. L., Borgnia, M. J., Stewart-Jones, G., Lee, M. S., Bronkema, N., Perfect, J., Moody, A., Wiehe, K., Bradley, T., Kepler, T. B., Alam, M., Parks, R. J., Foulger, A., Bonsignori, M., LaBranche, C. C., Montefiori, D. C., Seaman, M., Santra, S., Francica, J. R., Lynn, G. M., Aussedat, B., Walkowicz, W. E., Laga, R., Kelsoe, G., Saunders, K. O., Fera, D., Kwong, P. D., Seder, R. A., Bartesaghi, A., Shaw, G. M., Acharya, P., Haynes, B. F.. 2020-06-30. Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques. https://doi.org/10.1101/2020.06.30.178921

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