HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies
Author(s)
Steichen, Jon M.; Kulp, Daniel W.; Escolano, Amelia; Dosenovic, Pia; Stanfield, Robyn L.; McCoy, Laura E.; Ozorowski, Gabriel; Hu, Xiaozhen; Kalyuzhniy, Oleksandr; Briney, Bryan; Schiffner, Torben; Garces, Fernando; Freund, Natalia T.; Gitlin, Alexander D.; Menis, Sergey; Georgeson, Erik; Kubitz, Michael; Adachi, Yumiko; Jones, Meaghan; Mayer, Christian T.; Ward, Andrew B.; Burton, Dennis R.; Wilson, Ian A.; Irvine, Darrell J.; Nussenzweig, Michel C.; Schief, William R.; Tokatlian, Talar; Mutafyan, Andrew Ayk; Yun, Dong Soo; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/108143/Irvine_HIV%20vaccine.pdf.jpg?sequence=4&isAllowed=y)
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Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline-targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens.
Date issued
2016-09Department
Koch Institute for Integrative Cancer Research at MITJournal
Immunity
Publisher
Elsevier
Citation
Steichen, Jon M., Daniel W. Kulp, Talar Tokatlian, Amelia Escolano, Pia Dosenovic, Robyn L. Stanfield, Laura E. McCoy, et al. “HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies.” Immunity 45, no. 3 (September 2016): 483–496.
Version: Final published version
ISSN
1074-7613
1097-4180