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The role of humoral immunity in HIV infection - Understanding broadly neutralizing antibody evolution

English title The role of humoral immunity in HIV infection - Understanding broadly neutralizing antibody evolution
Applicant Trkola Alexandra
Number 152663
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 01.04.2014 - 31.03.2017
Approved amount 678'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Immunology, Immunopathology

Keywords (5)

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

Lay Summary (German)

Lead
Wie sich breit wirksame und hochpotente Antikörper mit Hemmwirkung gegen HIV im infizierten Patienten entwickeln.
Lay summary

In diesem Projekt haben wir es uns zum Ziel gesetzt, die Entwicklung sogenannter broadly neutralizing Antibodies (bNAbs) gegen HIV, also Antikörpern, die breite und hochwirksame, hemmende Aktivität gegen verschiedenste HIV Stämme aufweisen, im infizierten Patienten zu studieren. Neutralisierende  Antiköper sind von grossem Interesse, da sie die Grundlage für einen wirksamen Impfstoff gegen HIV bilden. Wir haben die Möglichkeit für unsere Studien die umfangreiche Daten- und Probenbank (Biobank)  der Schweizerischen HIV Kohorten Studie (SHCS) zu nutzen. Teilnehmer an diese Studie haben über die letzten mehr als 25 Jahre in anonymisierter Form Blutproben gespendet, die für bestimmte Forschungsvorhaben zur Verfügung stehen. Zusätzlich sind ebenfalls in anonymisierter Form Angaben zum Krankheitsverlauf und eine Vielzahl anderer Parameter betreffend der HIV Infektion der Teilnehmer verfügbar, die in unserem Fall eine gezielte Analyse der Parameter erlauben, die an der Bildung effizienter Antikörper mit Hemmwirkung gegen HIV, den bNAbs,  beteiligt sind. Dazu werden wir knapp 4000 Proben von Teilnehmern der SHCS Studie auf das Vorhandensein von bNAbs untersuchen. Die Antikörper werden in ihrer Reaktivität charakterisiert und die Antikörper von zehn Patienten mit der höchsten Hemmwirkung an Plasmaantikörpern kloniert. Ein spezifischer Schwerpunkt unserer Analysen wird auf die Charakterisierung der Antikörper gelegt, die eine bestimmte Region im HIV Hüllportein, die sogenannte membrane proximal external region (MPER), gerichtet sind. Diese Antikörper wären ein idealer Ausgangspunkt für einen Impfstoff da sie sehr breit wirksam sein können, d.h. alle genetischen Varianten von HIV erkennen können. Derzeit weiss man aber noch nicht wie diese Antikörper überhaupt entstehen können. Durch eine umfassende Studie dieser Antikörper in einer grossen Anzahl von Patienten hoffen wir Parameter definieren zu können, die die Entwicklung dieser Art von Antikörpern ermöglichen.

 

Direct link to Lay Summary Last update: 14.04.2014

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.
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.
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.
Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.
Beauparlant David, Rusert Peter, Magnus Carsten, Kadelka Claus, Weber Jacqueline, Uhr Therese, Zagordi Osvaldo, Oberle Corinna, Duenas-Decamp Maria J, Clapham Paul R, Metzner Karin J, Günthard Huldrych F, Trkola Alexandra (2017), Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality., in PLoS pathogens, 13(3), 1006255-1006255.
Determinants of HIV-1 broadly neutralizing antibody induction.
Rusert Peter, Kouyos Roger D, Kadelka Claus, Ebner Hanna, Schanz Merle, Huber Michael, Braun Dominique L, Hozé Nathanael, Scherrer Alexandra, Magnus Carsten, Weber Jacqueline, Uhr Therese, Cippa Valentina, Thorball Christian W, Kuster Herbert, Cavassini Matthias, Bernasconi Enos, Hoffmann Matthias, Calmy Alexandra, Battegay Manuel, Rauch Andri, Yerly Sabine, Aubert Vincent, Klimkait Thomas, Böni Jürg (2016), Determinants of HIV-1 broadly neutralizing antibody induction., in Nature medicine, 22(11), 1260-1267.
HIV-1 resistance to neutralizing antibodies: Determination of antibody concentrations leading to escape mutant evolution.
Magnus Carsten, Reh Lucia, Trkola Alexandra (2016), HIV-1 resistance to neutralizing antibodies: Determination of antibody concentrations leading to escape mutant evolution., in Virus Research, 218, 57-70.
Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs.
Oberle Corinna S, Joos Beda, Rusert Peter, Campbell Nottania K, Beauparlant David, Kuster Herbert, Weber Jacqueline, Schenkel Corinne D, Scherrer Alexandra U, Magnus Carsten, Kouyos Roger, Rieder Philip, Niederöst Barbara, Braun Dominique L, Pavlovic Jovan, Böni Jürg, Yerly Sabine, Klimkait Thomas, Aubert Vincent, Trkola Alexandra, Metzner Karin J, Günthard Huldrych F, Günthard Huldrych F (2016), Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs., in Retrovirology, 13(1), 62-62.
The HIV-1 Entry Process: A Stoichiometric View
Brandenberg Oliver F., Magnus Carsten, Regoes Roland R., Trkola Alexandra (2015), The HIV-1 Entry Process: A Stoichiometric View, in Trends in Microbiology, 23(12), 763-774.
Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent.
Reh Lucia, Magnus Carsten, Schanz Merle, Weber Jacqueline, Uhr Therese, Rusert Peter, Trkola Alexandra (2015), Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent., in PLoS pathogens, 11(7), 1004966-1004966.
Different infectivity of HIV-1 strains is linked to number of envelope trimers required for entry.
Brandenberg Oliver F, Magnus Carsten, Rusert Peter, Regoes Roland R, Trkola Alexandra (2015), Different infectivity of HIV-1 strains is linked to number of envelope trimers required for entry., in PLoS pathogens, 11(1), 1004595-1004595.
High-Throughput Sequencing of Human Immunoglobulin Variable Regions with Subtype Identification
Schanz Merle, Liechti Thomas, Zagordi Osvaldo, Miho Enkelejda, Reddy Sai T., Günthard Huldrych F., Trkola Alexandra, Huber Michael (2014), High-Throughput Sequencing of Human Immunoglobulin Variable Regions with Subtype Identification, in PLoS ONE, 9(11), e111726-e111726.

Collaboration

Group / person Country
Types of collaboration
Prof Dr med Huldrych Günthard/ Division of Infectious Diseases/ University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Dr Sai Reddy/ETHZ-DBSSE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Swiss HIV Cohort Study (SHCS)/PD. Dr Andri Rauch Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Dr med Jacques Fellay/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Dr John Robinson/ Institute of Organic Chemistry/University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Keystone Conference HIV vaccines Talk given at a conference Determinants of Broadly Neutralizing Antibody Development 26.03.2017 Steam Boat Springs, United States of America Schanz Merle Mareike; Kadelka Claus; Liechti Thomas; Trkola Alexandra; Ebner Hanna;
CROI Talk given at a conference The impact of HIV-1 genetics on imprinting antibody responses: The Swiss 4.5K Screen 13.02.2017 Seattle, United States of America Trkola Alexandra; Kadelka Claus; Liechti Thomas; Schanz Merle Mareike; Ebner Hanna;
CROI Talk given at a conference Virus, Host, and Disease Factors Govern HIV-1 Broadly Neutralizing Antibody Induction 24.02.2016 Boston, United States of America Schanz Merle Mareike; Liechti Thomas; Trkola Alexandra; Kadelka Claus; Ebner Hanna;
CROI Talk given at a conference Envelope Trimer Numbers Required for Entry Steer HIV-1 Infectivity and Entry Kinetics 22.02.2016 Seattle, United States of America Trkola Alexandra;
CROI Talk given at a conference HIV-specific binding antibody profiles associated with bnAb activity 13.02.2016 Seattle, United States of America Liechti Thomas; Ebner Hanna; Kadelka Claus; Schanz Merle Mareike; Trkola Alexandra;
Centes Gardes HIV Vaccine Talk given at a conference Virus, Host, and Disease Factors Govern HIV-1 Broadly Neutralizing Antibody Induction 25.10.2015 Annecy, France Liechti Thomas; Kadelka Claus; Ebner Hanna; Trkola Alexandra; Beauparlant David; Schanz Merle Mareike;
7th Blizard Institute HIV Symposium Talk given at a conference HIV-1 entry revisited 18.06.2015 London, Great Britain and Northern Ireland Beauparlant David; Schanz Merle Mareike; Trkola Alexandra; Reh Lucia;
5th Swiss Virology Meeting Talk given at a conference Efficacy Loss of Broadly Neutralizing Antibodies During HIV-1 Cell-to-Cell Transmission is Strain and Epitope Dependent 09.10.2014 Thun, Switzerland Trkola Alexandra; Reh Lucia;
5th Swiss Virology Meeting Talk given at a conference High tolerance to sequence variation allows precise and rapid definition of ELITE HIV neutralizing antibodies 09.10.2014 Thun, Switzerland Trkola Alexandra; Stiegeler Emanuel;


Associated projects

Number Title Start Funding scheme
172790 Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen 01.04.2017 Project funding (special)
135527 The role of humoral immunity in HIV infection 01.04.2011 Project funding (Div. I-III)
172790 Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen 01.04.2017 Project funding (special)

Abstract

Building on recent discoveries in the HIV antibody field, we propose here to conduct a systematic screen for broadly neutralizing antibody (bNAb) activity elicited during HIV infection using the extensive sample and data collection of the Swiss HIV Cohort Study. By assessing the neutralization breadth in approx. 3800 closely monitored individuals at different disease stages spanning the HIV infection of the past 25 years, we will have a unique possibility to address many aspects of neutralizing antibody evolution in HIV infection that urgently await clarification. In order to learn why bNAbs are so rarely induced in natural infection and to unravel how to induce them by vaccination, we need to identify and characterize more bNAbs, define their ontogeny, study their evolution over time and ideally, derive alongside information on the co-evolving viral envelope gene. A main goal of our study is to obtain insights why bNAb induction is generally rare in HIV infection. The comprehensive patient data and specimen that are available within the investigated patient cohorts will empower our study to perform extended systematic and longitudinal analyses that go beyond a mere frequency analysis of antibody responses and have the possibility to confirm and to rule out potential viral, host and disease linked co-factors of bNAb induction.Aim A focusses on the screening of the cohort for patients with broadly neutralizing plasma activity, determination of their binding antibody profiles and prediction of the recognized neutralization epitopes. This large screen is possible due to recent technical advances in the antibody discovery field that we will employ here, in particular a combination of high-throughput neutralization and binding antibody assays and computational prediction algorithms which allows to retrieve neutralizing antibody epitope information directly from plasma analysis. Finally, and most importantly, these data will be utilized to probe association of bNAb induction with viral, host and disease parameters. Within Aim B we propose to clone bNAbs from patients with top neutralizing activity in plasma and to study the ontogeny of these antibodies longitudinally alongside the autologous virus strain. Aim C focusses specifically on MPER specific antibodies. Here we seek to explore the factors that are associated with induction of this type of antibodies and to study their potential association with viral, host and disease factors. A particular emphasis will be on investigating the frequencies and phenotype of IgG1 and IGG3 MPER responses, as the MPER specific bNAbs are all of the otherwise amongst HIV envelope antibody uncommon IgG3 subclass. Secondly, we will investigate a potential association with autoreactive antibodies induced during HIV infection as several MPER antibodies are described to be strongly autoreactive. An in depth analysis of which viral, host and disease factors allow the emergence of bNAbs as we propose to conduct here is critical to harness these types for antibodies for vaccines.
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