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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.

2022-01-16 immunology
10.1101/2022.01.14.476215 bioRxiv
Show 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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