HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Jon M. Steichen; Daniel W. Kulp; Talar Tokatlian; Amelia Escolano; Pia Dosenovic; Robyn L. Stanfield; Laura E. McCoy; Gabriel Ozorowski; Xiaozhen Hu; Oleksandr Kalyuzhniy; Bryan Briney; Torben Schiffner; Fernando Garces; Natalia T. Freund; Alexander D. Gitlin; Sergey Menis; Erik Georgeson; Michael Kubitz; Yumiko Adachi; Meaghan Jones; Andrew A. Mutafyan; Dong Soo Yun; Christian T. Mayer; Andrew B. Ward; Dennis R. Burton; Ian A. Wilson; Darrell J. Irvine; Michel C. Nussenzweig; William R. Schief

doi:10.1016/j.immuni.2016.08.016

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Jon M. Steichen, Daniel W. Kulp, Talar Tokatlian, Amelia Escolano, Pia Dosenovic, Robyn L. Stanfield, Laura E. McCoy, Gabriel Ozorowski, Xiaozhen Hu, Oleksandr Kalyuzhniy, Bryan Briney, Torben Schiffner, Fernando Garces, Natalia T. Freund, Alexander D. Gitlin, Sergey Menis, Erik Georgeson, Michael Kubitz, Yumiko Adachi, Meaghan JonesAndrew A. Mutafyan, Dong Soo Yun, Christian T. Mayer, Andrew B. Ward, Dennis R. Burton, Ian A. Wilson, Darrell J. Irvine, Michel C. Nussenzweig^*, William R. Schief

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

296 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	483-496
Number of pages	14
Journal	Immunity
Volume	45
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2016.08.016
State	Published - 20 Sep 2016
Externally published	Yes

Funding

Funders	Funder number
National Institutes of Health
U.S. Department of Energy
National Institute of General Medical Sciences	P41GM103393, T32GM007739
National Institute of Allergy and Infectious Diseases	CHAVI-ID 1UM1AI100663, P01 AI110657, R01 AI084817
United States Agency for International Development
Bill and Melinda Gates Foundation
International AIDS Vaccine Initiative
Stanford University
Office of Science
Biological and Environmental Research
SLAC National Accelerator Laboratory
Ragon Institute of MGH, MIT and Harvard
Ministerie van Buitenlandse Zaken

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2016.08.016

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Steichen, J. M., Kulp, D. W., Tokatlian, T., Escolano, A., Dosenovic, P., Stanfield, R. L., McCoy, L. E., Ozorowski, G., Hu, X., Kalyuzhniy, O., Briney, B., Schiffner, T., Garces, F., Freund, N. T., Gitlin, A. D., Menis, S., Georgeson, E., Kubitz, M., Adachi, Y., ... Schief, W. R. (2016). HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies. Immunity, 45(3), 483-496. https://doi.org/10.1016/j.immuni.2016.08.016

@article{91784cbf13f14f8e8c807242d33e2264,

title = "HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies",

abstract = "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.",

author = "Steichen, {Jon M.} and Kulp, {Daniel W.} and Talar Tokatlian and Amelia Escolano and Pia Dosenovic and Stanfield, {Robyn L.} and McCoy, {Laura E.} and Gabriel Ozorowski and Xiaozhen Hu and Oleksandr Kalyuzhniy and Bryan Briney and Torben Schiffner and Fernando Garces and Freund, {Natalia T.} and Gitlin, {Alexander D.} and Sergey Menis and Erik Georgeson and Michael Kubitz and Yumiko Adachi and Meaghan Jones and Mutafyan, {Andrew A.} and Yun, {Dong Soo} and Mayer, {Christian T.} and Ward, {Andrew B.} and Burton, {Dennis R.} and Wilson, {Ian A.} and Irvine, {Darrell J.} and Nussenzweig, {Michel C.} and Schief, {William R.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = sep,

day = "20",

doi = "10.1016/j.immuni.2016.08.016",

language = "אנגלית",

volume = "45",

pages = "483--496",

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Steichen, JM, Kulp, DW, Tokatlian, T, Escolano, A, Dosenovic, P, Stanfield, RL, McCoy, LE, Ozorowski, G, Hu, X, Kalyuzhniy, O, Briney, B, Schiffner, T, Garces, F, Freund, NT, Gitlin, AD, Menis, S, Georgeson, E, Kubitz, M, Adachi, Y, Jones, M, Mutafyan, AA, Yun, DS, Mayer, CT, Ward, AB, Burton, DR, Wilson, IA, Irvine, DJ, Nussenzweig, MC & Schief, WR 2016, 'HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies', Immunity, vol. 45, no. 3, pp. 483-496. https://doi.org/10.1016/j.immuni.2016.08.016

TY - JOUR

T1 - HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

AU - Steichen, Jon M.

AU - Kulp, Daniel W.

AU - Tokatlian, Talar

AU - Escolano, Amelia

AU - Dosenovic, Pia

AU - Stanfield, Robyn L.

AU - McCoy, Laura E.

AU - Ozorowski, Gabriel

AU - Hu, Xiaozhen

AU - Kalyuzhniy, Oleksandr

AU - Briney, Bryan

AU - Schiffner, Torben

AU - Garces, Fernando

AU - Freund, Natalia T.

AU - Gitlin, Alexander D.

AU - Menis, Sergey

AU - Georgeson, Erik

AU - Kubitz, Michael

AU - Adachi, Yumiko

AU - Jones, Meaghan

AU - Mutafyan, Andrew A.

AU - Yun, Dong Soo

AU - Mayer, Christian T.

AU - Ward, Andrew B.

AU - Burton, Dennis R.

AU - Wilson, Ian A.

AU - Irvine, Darrell J.

AU - Nussenzweig, Michel C.

AU - Schief, William R.

PY - 2016/9/20

Y1 - 2016/9/20

N2 - 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.

AB - 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.

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ER -

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

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UN SDGs

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