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VACCINATION

bnAbs for HIV: shepherding towards improbable mutations

Nature Reviews Immunology volume 20, page 71 (2020)Cite this article

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The discovery of broadly neutralizing antibodies (bnAbs) to HIV in rare HIV-positive individuals indicated that it should be possible to design effective vaccines. However, this has proved to be exceptionally challenging since HIV-targeted bnAbs tend to have many unusual features, including ‘improbable mutations’ located outside the normal mutation hotspots. Moreover, the inferred precursors of the known bnAbs typically have no detectable affinity for the virus. Therefore, vaccination strategies need to first prime B cells encoding bnAb precursors, followed by immunogens that shepherd antibody affinity maturation towards the acquisition of unusual features. Two reports in Science now demonstrate the design of immunogens for such a vaccine strategy.

Informed by the crystal structure of BG18 bound to an Env trimer, as well as structural and functional information from cryo-electron microscopy (cryo-EM) and mutational studies, the authors were able to define the key genetic features that enable target recognition by BG18. These insights informed a bioinformatics approach to search for potential BG18 precursors in a next-generation sequencing dataset of >1 billion sequences of B cell receptor (BCR) heavy chains from 14 HIV-negative donors. Encouragingly, precursors were identified in all donors, and the sequence information of their HCDR3 domains was used to design BG18-like precursor antibodies.

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References

Original articles

  • Steichen, J. M. et al. A generalized HIV vaccine design strategy for priming broadly neutralizing antibody responses. Science 366, eaax4380 (2019)

    Article  CAS  Google Scholar 

  • Saunders, K. O. et al. Targeted selection of HIV-specific antibody mutations by engineering B cell maturation. Science 366, eaay7199 (2019)

    Article  CAS  Google Scholar 

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  1. Nature Reviews Immunology http://www.nature.com/nri/

    Alexandra Flemming

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  1. Alexandra Flemming
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Correspondence to Alexandra Flemming.

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Flemming, A. bnAbs for HIV: shepherding towards improbable mutations. Nat Rev Immunol 20, 71 (2020). https://doi.org/10.1038/s41577-019-0270-0

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