Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

Andrew T. McGuire; Matthew D. Gray; Pia Dosenovic; Alexander D. Gitlin; Natalia T. Freund; John Petersen; Colin Correnti; William Johnsen; Robert Kegel; Andrew B. Stuart; Jolene Glenn; Michael S. Seaman; William R. Schief; Roland K. Strong; Michel C. Nussenzweig; Leonidas Stamatatos

doi:https://doi.org/10.1038/ncomms10618

Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

Andrew T. McGuire, Matthew D. Gray, Pia Dosenovic, Alexander D. Gitlin, Natalia T. Freund, John Petersen, Colin Correnti, William Johnsen, Robert Kegel, Andrew B. Stuart, Jolene Glenn, Michael S. Seaman, William R. Schief, Roland K. Strong, Michel C. Nussenzweig, Leonidas Stamatatos

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

Abstract

VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.

Original language	English
Article number	10618
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10618
State	Published - 24 Feb 2016
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

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https://doi.org/10.1038/ncomms10618

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McGuire, A. T., Gray, M. D., Dosenovic, P., Gitlin, A. D., Freund, N. T., Petersen, J., Correnti, C., Johnsen, W., Kegel, R., Stuart, A. B., Glenn, J., Seaman, M. S., Schief, W. R., Strong, R. K., Nussenzweig, M. C., & Stamatatos, L. (2016). Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nature Communications, 7, Article 10618. https://doi.org/10.1038/ncomms10618

@article{3979c660fdfa49589b05393f5be4c4af,

title = "Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice",

abstract = "VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.",

author = "McGuire, {Andrew T.} and Gray, {Matthew D.} and Pia Dosenovic and Gitlin, {Alexander D.} and Freund, {Natalia T.} and John Petersen and Colin Correnti and William Johnsen and Robert Kegel and Stuart, {Andrew B.} and Jolene Glenn and Seaman, {Michael S.} and Schief, {William R.} and Strong, {Roland K.} and Nussenzweig, {Michel C.} and Leonidas Stamatatos",

note = "Funding Information: This research was funded by HIVRAD/P01 AI094419 and U19 AI109632 (L.S.), a CIHR Fellowship (A.T.M.), and an international post-doctoral fellowship from the Swedish Research Council (P.D.). We thank Chingwen Yang and Rada Norinsky at the gene targeting recourse centre at The Rockefeller University for their contribution on the generation of the knock-in mice.",

year = "2016",

month = feb,

day = "24",

doi = "https://doi.org/10.1038/ncomms10618",

language = "الإنجليزيّة",

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journal = "Nature Communications",

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McGuire, AT, Gray, MD, Dosenovic, P, Gitlin, AD, Freund, NT, Petersen, J, Correnti, C, Johnsen, W, Kegel, R, Stuart, AB, Glenn, J, Seaman, MS, Schief, WR, Strong, RK, Nussenzweig, MC & Stamatatos, L 2016, 'Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice', Nature Communications, vol. 7, 10618. https://doi.org/10.1038/ncomms10618

TY - JOUR

T1 - Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

AU - McGuire, Andrew T.

AU - Gray, Matthew D.

AU - Dosenovic, Pia

AU - Gitlin, Alexander D.

AU - Freund, Natalia T.

AU - Petersen, John

AU - Correnti, Colin

AU - Johnsen, William

AU - Kegel, Robert

AU - Stuart, Andrew B.

AU - Glenn, Jolene

AU - Seaman, Michael S.

AU - Schief, William R.

AU - Strong, Roland K.

AU - Nussenzweig, Michel C.

AU - Stamatatos, Leonidas

N1 - Funding Information: This research was funded by HIVRAD/P01 AI094419 and U19 AI109632 (L.S.), a CIHR Fellowship (A.T.M.), and an international post-doctoral fellowship from the Swedish Research Council (P.D.). We thank Chingwen Yang and Rada Norinsky at the gene targeting recourse centre at The Rockefeller University for their contribution on the generation of the knock-in mice.

PY - 2016/2/24

Y1 - 2016/2/24

N2 - VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.

AB - VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.

UR - http://www.scopus.com/inward/record.url?scp=84959378678&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/ncomms10618

DO - https://doi.org/10.1038/ncomms10618

M3 - مقالة

C2 - 26907590

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10618

ER -

Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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