B cells discriminate HIV-1 Envelope protein affinities by sensing antigen binding association rates

Hossain, M. A.; Anasti, K.; Watts, B.; Cronin, K.; Kane, A. P.; Edwards, R. J.; Easterhoff, D.; Zhang, J.; Rountree, W.; Ortiz, Y.; Verkoczy, L.; Reth, M.; Alam, S. M.

doi:10.1101/2022.01.14.476215

bioRxiv · 10.1101/2022.01.14.476215

B cells discriminate HIV-1 Envelope protein affinities by sensing antigen binding association rates

Hossain, M. A.·Anasti, K.·Watts, B.·Cronin, K.·Kane, A. P.·Edwards, R. J.·Easterhoff, D.·Zhang, J.·Rountree, W.·Ortiz, Y.·Verkoczy, L.·Reth, M.·Alam, S. M.

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Abstract

HIV-1 Envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role of affinities (equilibrium dissociation constant, KD) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during B cell activation is based solely on Env protein binding KD, and whether B cells discriminate between proteins of similar affinities but that bind with different kinetic rates. Here we used a panel of Env proteins and Ramos B cell lines expressing IgM BCRs with specificity for CD4 binding-site broadly neutralizing (bnAb) or a precursor antibody to study the role of antigen binding kinetic rates on both early (proximal/distal signaling) and late events (BCR/antigen internalization) in B cell activation. Our results support a kinetic model for B cell activation in which Env protein affinity discrimination is based not on overall KD, but on sensing of association rate and a threshold antigen-BCR half-life.

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Hossain, M. A., Anasti, K., Watts, B., Cronin, K., Kane, A. P., Edwards, R. J., Easterhoff, D., Zhang, J., Rountree, W., Ortiz, Y., Verkoczy, L., Reth, M., Alam, S. M.. 2022-01-16. B cells discriminate HIV-1 Envelope protein affinities by sensing antigen binding association rates. https://doi.org/10.1101/2022.01.14.476215

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