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The role of humoral immunity in HIV infection

English title The role of humoral immunity in HIV infection
Applicant Trkola Alexandra
Number 135527
Funding scheme Project funding
Research institution Institute of Medical Virology Universtity of Zurich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.04.2011 - 31.03.2014
Approved amount 468'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Immunology, Immunopathology

Keywords (4)

HIV; Immune response; vaccine; neutralization

Lay Summary (English)

Lead
Lay summary

HIV infection, knowledge of which is key to vaccine design.in It is generally acknowledged that an effective HIV vaccine will need to incorporate protective antibody responses. Which type of antibody responses will be needed, which breadth and potency these responses need to have and how they can be elicited awaits however further definition. In the present proposal we aim to obtain mechanistic insights into the modes of action of neutralizing antibodies, antibodies which by binding to the virus inactivate it. We will further explore antibody responses to HIV which by binding to viral proteins on infected cells mobilize killer cells of the immune system and mediate killing of the infected cells. A specific focus will be put on defining how HIV succeeds in shielding its surface proteins from recognition by neutralizing antibodies. One prominent way the virus uses is shielding of neutralization sensitive domains on gp120 by the variable loops 1 and 2 on the surface protein gp120. Here we will explore how the V1V2 steers sensitivity of the virus to neutralization.  With these studies we aim to unravel central aspects of the mechanisms underlying the antiviral activity of the antibody response

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors.
Mann Axel, Friedrich Nikolas, Krarup Anders, Weber Jacqueline, Stiegeler Emanuel, Dreier Birgit, Pugach Pavel, Robbiani Melissa, Riedel Tina, Moehle Kerstin, Robinson John A, Rusert Peter, Plückthun Andreas, Trkola Alexandra (2013), Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors., in Journal of virology, 87(10), 5868-81.
Mathematical models: a key to understanding HIV envelope interactions?
Magnus Carsten, Brandenberg Oliver F, Rusert Peter, Trkola Alexandra, Regoes Roland R (2013), Mathematical models: a key to understanding HIV envelope interactions?, in Journal of immunological methods, 398-399, 1-18.
Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies.
Abela Irene A, Berlinger Livia, Schanz Merle, Reynell Lucy, Günthard Huldrych F, Rusert Peter, Trkola Alexandra (2012), Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies., in PLoS pathogens, 8(4), 1002634-1002634.
HIV vaccines: an attainable goal?
Reynell Lucy, Trkola Alexandra (2012), HIV vaccines: an attainable goal?, in Swiss medical weekly, 142, 13535-13535.
Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies.
Rusert Peter, Krarup Anders, Magnus Carsten, Brandenberg Oliver F, Weber Jacqueline, Ehlert Anna-Katharina, Regoes Roland R, Günthard Huldrych F, Trkola Alexandra (2011), Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies., in The Journal of experimental medicine, 208(7), 1419-33.
Synthetic virus-like particles and conformationally constrained peptidomimetics in vaccine design.
Riedel Tina, Ghasparian Arin, Moehle Kerstin, Rusert Peter, Trkola Alexandra, Robinson John A (2011), Synthetic virus-like particles and conformationally constrained peptidomimetics in vaccine design., in Chembiochem : a European journal of chemical biology, 12(18), 2829-36.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
AIDS Vaccine 2013 Talk given at a conference Neutralization of Diverse HIV Strains by V3 Specific DARPins with Different Structural Preferences in Epitope Recognition 07.10.2013 Barcelona, Spain Trkola Alexandra;
AIDS Vaccine 2013 Talk given at a conference The V1V2 Domain Preserves Envelope Functionality During Free Virus Transmission but Is Largely Dispensable for Cell-Cell Transmission 07.10.2013 Barcelona, Spain Brandenberg Oliver; Trkola Alexandra;
AIDS VAccine 2013 Talk given at a conference Highly potent broadly neutralizing antibodies lack potential to inhibit HIV-1 cell-to-cell transmission 07.10.2013 Barcelona, Spain Trkola Alexandra; Schanz Merle Mareike;
SSM Interlaken 2013 Talk given at a conference The impact of cell-to-cell transmission in HIV infection Safe heaven for the virus – obstacle for inhibitors and vaccines 26.06.2013 Interlaken, Switzerland Brandenberg Oliver; Trkola Alexandra;
Döak Talk given at a conference Cell-to-cell spread of HIV Safe heaven for the virus – obstacle for inhibitors and vaccines 12.06.2013 Innsbruck, Austria Trkola Alexandra; Brandenberg Oliver;
Gordon Conference Viruses&Cells Talk given at a conference Shedding light on HIV neutralization The impact of cell to cell transmission 05.05.2013 Barga, Italy Brandenberg Oliver; Trkola Alexandra;
Swiss Virology meeting Talk given at a conference HIV env variable loops 1 and 2 (V1V2): Regulators of the HIV entry process and antibody evasion in free virus infection and cell-cell transmission 05.02.2013 Thun, Switzerland Trkola Alexandra; Brandenberg Oliver;
Swiss Virology meeting Poster Identification and characterization of HIV-1 neutralizing antibodies 05.02.2013 Thun, Switzerland Schanz Merle Mareike; Trkola Alexandra;
Swiss Virology meeting Poster The role of ADCC in HIV infection 05.02.2013 Thun, Switzerland, Switzerland Liechti Thomas; Trkola Alexandra;
Workshop on Mucosal Immunology, HIV Vaccines and Microbicides Talk given at a conference Shedding light on neutralization 13.11.2012 Hluhluwe, South Africa, South Africa Trkola Alexandra;
AIDS Vaccine 2012 Poster Conformation-Dependent Recognition of HIV Gp120 by Designed Ankyrin Repeat Proteins Provides Novel Possibilities to Develop Distinct HIV Entry Inhibitors 09.09.2012 Boston, MA, USA, United States of America Trkola Alexandra;


Associated projects

Number Title Start Funding scheme
152663 The role of humoral immunity in HIV infection - Understanding broadly neutralizing antibody evolution 01.04.2014 Project funding (special)
172790 Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen 01.04.2017 Project funding (special)
120739 The role of humoral immunity in HIV infection 01.04.2008 Project funding

Abstract

An effective HIV vaccine will need to incorporate protective antibody responses. Which type of responses, neutralizing, effector function inducing, which epitopes specificities, which breadth and potency these responses need to have and how they can be elicited awaits however further definition. In the present proposal we aim to obtain mechanistic insights into the modes of action of neutralizing antibodies (Aim A), derive information on the functionality of the humoral immune response to HIV in eliciting effector functions (Aim B), and to define the influence of the V1V2 domain of gp120 in steering the neutralization response against HIV (Aim C). Our studies will be based on both, in vitro studies using well defined monoclonal antibodies and ex vivo studies, based on the characterization of the developing humoral immune response from acute to chronic HIV infection. With these studies we aim to unravel central aspects of the mechanisms underlying the antiviral activity of the humoral immune response in vivo, knowledge of which is key to vaccine design.Aim A: Within this aim we propose to explore several mechanistic features of the inhibitory processes of neutralizing moncolonal antibodies directed to diverse epitopes and polyclonal responses elicited during HIV infection in vivo. We will analyze the kinetics of the neutralization process in both cell-free and cell-cell virus transmission and determine whether or not neutralization is irreversible. Building upon our recent discovery that MPER antibodies 2F5 and 4E10 inactivate HIV irreversibly by inducing gp120 shedding, we will explore the relevance of gp120 shedding induction in the neutralization process of diverse antibodies. By assessing the effects of neutralizing antibodies on virus pre- and post attachment to target cells, and during cell-cell transmission, we aim to gain a complete picture on the functionality of neutralizing antibodies at these steps of the virus life cycle. We will further expand our studies on the stoichiometry of neutralization to explore whether antibodies need to occupy one or more of their potential binding sites on the trimeric spike in order to inhibit HIV entry, cause irreversible neutralization or induce shedding.Aim B: Within this research aim we propose to investigate the role of effector functions mediated by the humoral immune response. A particularly emphasis will be put towards studying the interaction of HIV with professional phagocytes (monocyte derived macrophages and neutrophils) to determine the efficacy by which antibodies against HIV trigger phagocytic clearing. We will further assess the effects of antibodies on infected cells by assessing their capacity to elicit ADCC, ADCVI and inactivate progeny virus.Aim C: Within Aim C we propose a series of studies to define the role of the V1V2 loop within gp120 in steering sensitivity to neutralization. Specifically we will aim to i) Dissect monoclonal antibody specificities and polyclonal antibody responses elicited during HIV infection that depend or are counteracted by the V1V2 domain, ii) Define the mode of epitope shielding employed by the V1V2 loop in regulating the neutralization response, iii) Investigate the intra-patient evolution of the V1V2 domain and neutralizing antibody responses side by side, iv) Obtain functional insights into the role of the V1V2 loop in the entry process. These studies will provide us with detailed information how the V1V2 evolves to counteract neutralizing antibody responses elicited in vivo, which antibody responses are affected and may further allow definition of potential strategies for directing vaccine elicited responses to overcome restriction by the V1V2 loop.
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