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Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen

English title Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen
Applicant Trkola Alexandra
Number 172790
Funding scheme Project funding (special)
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.04.2017 - 31.03.2021
Approved amount 904'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Immunology, Immunopathology

Keywords (6)

large nested project SHCS; HIV; immune response; large nested project SHCS; vaccine; neutralization

Lay Summary (German)

Lead
Welche Faktoren betsimmen dei Entwicklung von broadly neutralizing antibodies (bnAbs) gegen HIV?Durch eine systematsiche Analyse von Virus, Immunantworten in HIV- Infizierten, die bnAbs ausgebildet haben, wollen wir dieser Fragestellung auf die Spur kommen.
Lay summary

Unser Projekt baut auf der bis dato grössten Studie zur Prävalenz von sogenannten broadly neutralizing Antibodies (bnAbs) aus, die bisher durchgeführt wurde. Im Swiss 4.5K Screen, den wir zusammen mit anderen Schweizer Wissenschaftlern durchgeführt hatten (Rusert, Kouyos et al Nat Med 2016), haben wir in knapp 4500 HIV-1 infizierten Patienten untersucht, welche Faktoren die Entwicklung von bnAbs beeinflussen. Das ist von grossem Interesse, da bnAbs auf Grund ihrer hervorragenden Eigenschaften, HIV-1 unterschiedlichster genetischer Stämme hemmen zu können, als ein Eckpfeiler eines wirksamen HIV Impfstoffes angesehen werden und diese Antikörper auch als Therapeutika von Interesse sind. Bis jetzt ist es jedoch noch nicht gelungen, bnAbs durch Impfstrategien hervorzurufen. Limitierend in der Entwicklung eines bnAb stimulierenden Impfstoffes ist insbesondere, dass wir nicht wissen, wie diese Antikörper in der natürlichen HIV-1 Infektion entstehen. Nur wenige Infizierte bilden diese hochwirksamen Antikörper aus. Zu definieren wo die Restriktionen für die Entwicklung dieser Antikörper in vivo liegen, und damit potenziell Wege zu finden, wie dies in einer Impfung überwunden werden kann, ist das Ziel unserer Studien. Dazu werden wir eine Vielzahl von Aspekten untersuchen, die zum einen auf die Antikörperantworten selbst zielen, als auch auf die Patientenviren, die sie hervorrufen. Sind zum einen die Identifikation von Wirtsparamatern oder Infektionsspezifischen Faktoren ein Fokus unserer Untersuchung, ist ein weiterer Schwerpunkt auf die Viren, respektive die Hüllproteine der Viren in Patienten, die bnAb ausgebildet haben, gerichtet. Gelänge es Hüllproteine zu isolieren, die spezifische Determinanten tragen, die das Hervorrufen einer bnAb Antwort begünstigen, wäre das ein Meilenstein in der HIV Impfstoffentwicklung.

Direct link to Lay Summary Last update: 06.04.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells
Liechti Thomas, Kadelka Claus, Braun Dominique L., Kuster Herbert, Böni Jürg, Robbiani Melissa, Günthard Huldrych F., Trkola Alexandra (2019), Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells, in The Journal of Experimental Medicine, 216(9), 2071-2090.
Correlates of broadly neutralizing antibody development
Abela Irene A., Kadelka Claus, Trkola Alexandra (2019), Correlates of broadly neutralizing antibody development, in Current Opinion in HIV and AIDS, 14(4), 279-285.
Lower Broadly Neutralizing Antibody Responses in Female Versus Male HIV-1 Infected Injecting Drug Users
Euler Zelda, VAN DEN KERKHOF Tom L., KOUYOS Roger D., TULLY Damien C., ALLEN Todd M., TRKOLA Alexandra, SANDERS Rogier W., SCHUITEMAKER Hanneke, VAN GILS Marit J. (2019), Lower Broadly Neutralizing Antibody Responses in Female Versus Male HIV-1 Infected Injecting Drug Users, in Viruses, 11(4), 384-384.
CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity
Ivan Branislav, Sun Zhaozhi, Subbaraman Harini, Friedrich Nikolas, Trkola Alexandra (2019), CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity, in PLOS Biology, 17(1), e3000114-e3000114.
Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy?
Subbaraman Harini, Schanz Merle, Trkola Alexandra (2018), Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy?, in Retrovirology, 15(1), 52-52.
Tracing HIV-1 strains that imprint broadly neutralizing antibody responses
Kouyos Roger D., Rusert Peter, Kadelka Claus, Huber Michael, Marzel Alex, Ebner Hanna, Schanz Merle, Liechti Thomas, Friedrich Nikolas, Braun Dominique L., Scherrer Alexandra U., Weber Jacqueline, Uhr Therese, Baumann Nicolas S., Leemann Christine, Kuster Herbert, Chave Jean-Philippe, Cavassini Matthias, Bernasconi Enos, Hoffmann Matthias, Calmy Alexandra, Battegay Manuel, Rauch Andri, Yerly Sabine, Aubert Vincent, KlimkaitThomas, BöniJürg, MetznerKarin, GünthardHuldrych, TrkolaAlexandra, the Swiss HIV Cohort (2018), Tracing HIV-1 strains that imprint broadly neutralizing antibody responses, in Nature, 561(7723), 406-410.
OMIP-047: High-Dimensional phenotypic characterization of B cellsOMIP-047
Liechti Thomas, Günthard Huldrych F., Trkola Alexandra (2018), OMIP-047: High-Dimensional phenotypic characterization of B cellsOMIP-047, in Cytometry Part A, 93(6), 592-596.
Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity
Kadelka Claus, Liechti Thomas, Ebner Hanna, Schanz Merle, Rusert Peter, Friedrich Nikolas, Stiegeler Emanuel, Braun Dominique L., Huber Michael, Scherrer Alexandra U., Weber Jacqueline, Uhr Therese, Kuster Herbert, Misselwitz Benjamin, Cavassini Matthias, Bernasconi Enos, Hoffmann Matthias, Calmy Alexandra, Battegay Manuel, Rauch Andri, Yerly Sabine, Aubert Vincent, Klimkait Thomas, Böni Jürg, Kouyos Roger, GünthardHuldrych, TrkolaAlexandra, the Swiss HIV Cohort (2018), Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity, in The Journal of Experimental Medicine, 215(6), 1589-1608.
Development of a high-throughput bead based assay system to measure HIV-1 specific immune signatures in clinical samples
Liechti Thomas, Kadelka Claus, Ebner Hanna, Friedrich Nikolas, Kouyos Roger D., Günthard Huldrych F., Trkola Alexandra (2018), Development of a high-throughput bead based assay system to measure HIV-1 specific immune signatures in clinical samples, in Journal of Immunological Methods, 454, 48-58.
Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage
Reh Lucia, Magnus Carsten, Kadelka Claus, Kühnert Denise, Uhr Therese, Weber Jacqueline, Morris Lynn, Moore Penny L., Trkola Alexandra (2018), Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage, in PLOS Pathogens, 14(1), e1006825-e1006825.

Collaboration

Group / person Country
Types of collaboration
Prof. Ralf Wagner/University of Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Andreas Plückthun/University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Dr. Peter Kwong/Vaccine Research Center/NIH United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Winfried Weissenhorn/University of Grenoble France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Quentin Sattentau/University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar in Medical Virology, University of Vienna Individual talk Paths to broad neutralization of HIV-1 26.11.2019 Vienna, Austria Trkola Alexandra;
Symposium 80 Years of Archives of Virology Talk given at a conference Paths to broad neutralization of HIV-1 25.11.2019 Vienna, Austria Trkola Alexandra;
Cent Gardes Conference: HIV Vaccines Talk given at a conference Paths to broad neutralization of HIV-1 30.09.2019 Veyrier du Lac, France Trkola Alexandra;
Annual Swiss Society for Microbiology Meeting Talk given at a conference Novel broadly neutralizing inhibitors pave the way for HIV-1 vaccine design 03.09.2019 Zürich, Switzerland Trkola Alexandra;
Seminar Institute Pasteur Individual talk Imprinting broadly neutralizing antibody responses to HIV-1 16.04.2019 Paris, France Trkola Alexandra;
29th Challenge in Virology Talk given at a conference Imprinting broadly neutralizing antibody responses to HIV-1 11.01.2019 Grindelwald, Switzerland Trkola Alexandra;
Seminar series University College London Individual talk Imprinting broadly neutralizing antibody responses to HIV-1 19.11.2018 London, Great Britain and Northern Ireland Trkola Alexandra;
22nd International AIDS Conference (AIDS 2018) Talk given at a conference Factors determining bnAb elicitation in HIV-infected individuals during natural infection: Challenges a vaccine has to overcome 23.07.2018 Amsterdam, Netherlands Trkola Alexandra;
CROI 2018, Conference on Retroviruses and Opportunistic Infections Talk given at a conference Advances in immunology 04.03.2018 Boston, United States of America Trkola Alexandra;
7th Swiss Virology Meeting Poster Sequential receptor-induced conformational states of native membrane-embedded HIV-1 Env  30.01.2018 Fribourg, Switzerland Branislav Ivan; Trkola Alexandra;
Translational Medicine Conference Talk given at a conference HIV-1 Broadly Neutralizing Antibodies: Translating natural infection to effective vaccines and therapeutics 22.01.2018 Zürich, Switzerland Trkola Alexandra;
HIV Research for Prevention 2018: From Research to Impact (HIVR4P) Talk given at a conference Phenotypic Deficits in the HIV-1 Envelope Are Associated with the Maturation of a V2- Directed Broadly Neutralizing Antibody Lineage 22.01.2018 Madrid, Spain Trkola Alexandra; Reh Lucia;
Congreso Nacional GESIDA Talk given at a conference HIV-1 Broadly Neutralizing Antibodies: Hype, Hopes & Hurdles 28.11.2017 Vigo, Spain Trkola Alexandra;
AIDS Vaccine Research Subcommittee: Potential importance of cell-associated HIV for prevention strategies Talk given at a conference Impact of cell-cell transmission on bnAb neutralization and HIV-1 escape 13.09.2017 Rockville, United States of America Trkola Alexandra;
Seminar Vaccine Research Center Individual talk Determinants of Broadly Neutralizing Antibody Development 12.09.2017 Bethesda, United States of America Trkola Alexandra;
9th IAS Conference on HIV Science Poster A unique N332 supersite directed bnAb from a slow progressors shares characteristics with both CD4bs and V3-glycan bnAbs 23.07.2017 Paris, France Trkola Alexandra; Ebner Hanna;
9th IAS Conference on HIV Science Talk given at a conference Sequential receptor-induced conformational states of native membrane-embedded HIV-1 Env 23.07.2017 Paris, France Branislav Ivan; Trkola Alexandra;


Awards

Title Year
The 2018 Award of the Swiss Society for Infectious Diseases & SAFE-ID in the category basic reseach in infectious diseases 1st Prize 2018

Associated projects

Number Title Start Funding scheme
62030 Interactions between HIV-1, glycosaminoglycans and the CC-chemo- kine RANTES: Implications for the early steps in virus life cycle 01.10.2000 Project funding (Div. I-III)
156902 Transmission of influenza virus from asymptomatic healthcare workers and inpatients in the acute care hospital setting: A prospective study over two consecutive influenza seasons 01.05.2015 Project funding (Div. I-III)
152663 The role of humoral immunity in HIV infection - Understanding broadly neutralizing antibody evolution 01.04.2014 Project funding (special)
201266 Imprinting broadly neutralizing antibody responses to HIV-1 01.04.2021 Project funding (special)
135527 The role of humoral immunity in HIV infection 01.04.2011 Project funding (Div. I-III)
152663 The role of humoral immunity in HIV infection - Understanding broadly neutralizing antibody evolution 01.04.2014 Project funding (special)
102647 HIV entry: a target for the host immune response and antiviral approaches 01.03.2004 SNSF Professorships
120739 The role of humoral immunity in HIV infection 01.04.2008 Project funding (Div. I-III)

Abstract

Over the previous grant period we conducted a systematic survey of broadly neutralizing antibody (bnAb) activity in 4,484 HIV-1 infected individuals enrolled in two Swiss HIV cohorts, the Swiss HIV Cohort Study (SHCS) and the Zurich Primary HIV Infection Study (ZPHI). This largest HIV bnAb survey to date, now termed the Swiss 4.5K Screen, made several important and thought-provoking observations (see Rusert, Kouyos et al Nat Med 2016). In the current grant application we will continue the analysis of the Swiss 4.5K Screen, exploring additional parameters and concepts that relate to bnAb induction. Due to the comprehensive data sets available through the Swiss 4.5K Screen several of the topics we will investigate can be systematically addressed for the first time. To define how bnAbs can be best identified and what factors are linked with their induction, we will engage in a series of combined experimental and mathematical analyses to explore improved ways for delineating bnAb responses in polyclonal plasma and defining strategies that allow reliable and ideally also early detection of neutralization breadth development. The latter will be particularly useful for forthcoming vaccine efficacy testing. We will conduct a detailed analysis of HIV-1 binding antibody patterns in order to define antibody signatures that may be linked with bnAb appearance and to probe the influence of the host genome and other viral, disease and host factors on bnAb induction.The Swiss 4.5K Screen identified 239 bnAb inducers - the largest cohort of bnAb inducers thus far. Amongst these individuals we identified several patient groups of high interest including transmission pairs, viral load controllers and superinfection cases. Studying bnAb evolution in these patient groups bears unique potential to understand drivers and consequences of bnAb induction and evolution. Concentrating on the analysis of the virus envelope (Env) in the same set of bnAb inducer patients we aim to unravel how Envs from different subtypes steer bnAb specificity by conducting a comprehensive genotypic and phenotypic characterization of bnAb inducer Envs aiming to define Env features that trigger specificity. A second emphasis will lie on the investigation of bnAb transmission pairs to potentially derive what we refer to as bnAb imprinter Env - an Env that bears the capacity to mount the same bnAb response across individuals.
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