Assessing immunogenicity barriers of the HIV-1 envelope trimer

Liridona Maliqi; Nikolas Friedrich; Matthias Glögl; Stefan Schmutz; Daniel Schmidt; Peter Rusert; Merle Schanz; Maryam Zaheri; Chloé Pasin; Cyrille Niklaus; Caio Foulkes; Thomas Reinberg; Birgit Dreier; Irene Abela; David Peterhoff; Alexandra Hauser; Roger D. Kouyos; Huldrych F. Günthard; Marit J. van Gils; Rogier W. Sanders; Ralf Wagner; Andreas Plückthun; Alexandra Trkola

doi:https://doi.org/10.1038/s41541-023-00746-3

Assessing immunogenicity barriers of the HIV-1 envelope trimer

Liridona Maliqi, Nikolas Friedrich, Matthias Glögl, Stefan Schmutz, Daniel Schmidt, Peter Rusert, Merle Schanz, Maryam Zaheri, Chloé Pasin, Cyrille Niklaus, Caio Foulkes, Thomas Reinberg, Birgit Dreier, Irene Abela, David Peterhoff, Alexandra Hauser, Roger D. Kouyos, Huldrych F. Günthard, Marit J. van Gils, Rogier W. SandersRalf Wagner, Andreas Plückthun, Alexandra Trkola

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

Abstract

Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

Original language	English
Article number	148
Journal	npj Vaccines
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41541-023-00746-3
Publication status	Published - 1 Dec 2023

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Maliqi, L., Friedrich, N., Glögl, M., Schmutz, S., Schmidt, D., Rusert, P., Schanz, M., Zaheri, M., Pasin, C., Niklaus, C., Foulkes, C., Reinberg, T., Dreier, B., Abela, I., Peterhoff, D., Hauser, A., Kouyos, R. D., Günthard, H. F., van Gils, M. J., ... Trkola, A. (2023). Assessing immunogenicity barriers of the HIV-1 envelope trimer. npj Vaccines, 8(1), Article 148. https://doi.org/10.1038/s41541-023-00746-3

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title = "Assessing immunogenicity barriers of the HIV-1 envelope trimer",

abstract = "Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.",

author = "Liridona Maliqi and Nikolas Friedrich and Matthias Gl{\"o}gl and Stefan Schmutz and Daniel Schmidt and Peter Rusert and Merle Schanz and Maryam Zaheri and Chlo{\'e} Pasin and Cyrille Niklaus and Caio Foulkes and Thomas Reinberg and Birgit Dreier and Irene Abela and David Peterhoff and Alexandra Hauser and Kouyos, {Roger D.} and G{\"u}nthard, {Huldrych F.} and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Ralf Wagner and Andreas Pl{\"u}ckthun and Alexandra Trkola",

note = "Funding Information: A.T. received financial support for this study by the Swiss National Science Foundation (SNF #314730_172790). Additional financial support came from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement No. 681032 (to A.T. and R.W.) and from the Swiss government (through SERI) under grant agreement No.15.0337 (to A.T.). The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. This study was co-financed within the framework of the Swiss HIV Cohort Study, supported by the SNF (# 33CS30_201369 to H.F.G.), by the small nested SHCS project 744 (to A.T.) and by the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The SHCS data are collected by the five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers ). We thank the patients participating in the SHCS and their physicians and study nurses for patient care. We thank Jacqueline Weber and Mich{\`e}le Sickmann for technical assistance, and Sven Furler, Thamar Looser, Jonas V. Schaefer, Joana Marinho, Cristian Thom, and Sylvie Briand-Schumacher for planning and carrying out the high-throughput ribosome display selections. Funding Information: A.T. received financial support for this study by the Swiss National Science Foundation (SNF #314730_172790). Additional financial support came from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement No. 681032 (to A.T. and R.W.) and from the Swiss government (through SERI) under grant agreement No.15.0337 (to A.T.). The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. This study was co-financed within the framework of the Swiss HIV Cohort Study, supported by the SNF (# 33CS30_201369 to H.F.G.), by the small nested SHCS project 744 (to A.T.) and by the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The SHCS data are collected by the five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers). We thank the patients participating in the SHCS and their physicians and study nurses for patient care. We thank Jacqueline Weber and Mich{\`e}le Sickmann for technical assistance, and Sven Furler, Thamar Looser, Jonas V. Schaefer, Joana Marinho, Cristian Thom, and Sylvie Briand-Schumacher for planning and carrying out the high-throughput ribosome display selections. Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

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doi = "https://doi.org/10.1038/s41541-023-00746-3",

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Maliqi, L, Friedrich, N, Glögl, M, Schmutz, S, Schmidt, D, Rusert, P, Schanz, M, Zaheri, M, Pasin, C, Niklaus, C, Foulkes, C, Reinberg, T, Dreier, B, Abela, I, Peterhoff, D, Hauser, A, Kouyos, RD, Günthard, HF, van Gils, MJ , Sanders, RW, Wagner, R, Plückthun, A & Trkola, A 2023, 'Assessing immunogenicity barriers of the HIV-1 envelope trimer', npj Vaccines, vol. 8, no. 1, 148. https://doi.org/10.1038/s41541-023-00746-3

TY - JOUR

T1 - Assessing immunogenicity barriers of the HIV-1 envelope trimer

AU - Maliqi, Liridona

AU - Friedrich, Nikolas

AU - Glögl, Matthias

AU - Schmutz, Stefan

AU - Schmidt, Daniel

AU - Rusert, Peter

AU - Schanz, Merle

AU - Zaheri, Maryam

AU - Pasin, Chloé

AU - Niklaus, Cyrille

AU - Foulkes, Caio

AU - Reinberg, Thomas

AU - Dreier, Birgit

AU - Abela, Irene

AU - Peterhoff, David

AU - Hauser, Alexandra

AU - Kouyos, Roger D.

AU - Günthard, Huldrych F.

AU - van Gils, Marit J.

AU - Sanders, Rogier W.

AU - Wagner, Ralf

AU - Plückthun, Andreas

AU - Trkola, Alexandra

N1 - Funding Information: A.T. received financial support for this study by the Swiss National Science Foundation (SNF #314730_172790). Additional financial support came from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 681032 (to A.T. and R.W.) and from the Swiss government (through SERI) under grant agreement No.15.0337 (to A.T.). The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. This study was co-financed within the framework of the Swiss HIV Cohort Study, supported by the SNF (# 33CS30_201369 to H.F.G.), by the small nested SHCS project 744 (to A.T.) and by the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The SHCS data are collected by the five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers ). We thank the patients participating in the SHCS and their physicians and study nurses for patient care. We thank Jacqueline Weber and Michèle Sickmann for technical assistance, and Sven Furler, Thamar Looser, Jonas V. Schaefer, Joana Marinho, Cristian Thom, and Sylvie Briand-Schumacher for planning and carrying out the high-throughput ribosome display selections. Funding Information: A.T. received financial support for this study by the Swiss National Science Foundation (SNF #314730_172790). Additional financial support came from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 681032 (to A.T. and R.W.) and from the Swiss government (through SERI) under grant agreement No.15.0337 (to A.T.). The opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. This study was co-financed within the framework of the Swiss HIV Cohort Study, supported by the SNF (# 33CS30_201369 to H.F.G.), by the small nested SHCS project 744 (to A.T.) and by the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The SHCS data are collected by the five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed in http://www.shcs.ch/180-health-care-providers). We thank the patients participating in the SHCS and their physicians and study nurses for patient care. We thank Jacqueline Weber and Michèle Sickmann for technical assistance, and Sven Furler, Thamar Looser, Jonas V. Schaefer, Joana Marinho, Cristian Thom, and Sylvie Briand-Schumacher for planning and carrying out the high-throughput ribosome display selections. Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

AB - Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

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DO - https://doi.org/10.1038/s41541-023-00746-3

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SN - 1476-0584

VL - 8

JO - npj Vaccines

JF - npj Vaccines

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ER -

Assessing immunogenicity barriers of the HIV-1 envelope trimer

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