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Persistent Immunogenicity of Integrase Defective Lentiviral Vectors delivering membrane tethered Native-Like HIV-1 Envelope Trimers

View ORCID ProfileAlessandra Gallinaro, View ORCID ProfileMaria Franca Pirillo, View ORCID ProfileYoann Aldon, View ORCID ProfileSerena Cecchetti, View ORCID ProfileZuleika Michelini, View ORCID ProfileAntonella Tinari, View ORCID ProfileMartina Borghi, View ORCID ProfileAndrea Canitano, View ORCID ProfilePaul F. McKay, View ORCID ProfileRoberta Bona, View ORCID ProfileMaria Fenicia Vescio, View ORCID ProfileFelicia Grasso, View ORCID ProfileMaria Blasi, View ORCID ProfileSilvia Baroncelli, View ORCID ProfileGabriella Scarlatti, View ORCID ProfileCelia LaBranche, View ORCID ProfileDavid Montefiori, View ORCID ProfileMary E. Klotman, View ORCID ProfileRogier W. Sanders, View ORCID ProfileRobin J. Shattock, View ORCID ProfileDonatella Negri, View ORCID ProfileAndrea Cara
doi: https://doi.org/10.1101/2021.10.08.462761
Alessandra Gallinaro
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Alessandra Gallinaro
Maria Franca Pirillo
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Maria Franca Pirillo
Yoann Aldon
2Imperial College London, Department of Infectious Disease, Norfolk Place, London, UK
12Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, the Netherlands
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Serena Cecchetti
3Confocal Microscopy Unit NMR, Confocal Microscopy Area Core Facilities, Istituto Superiore di Sanità, Rome, Italy
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Zuleika Michelini
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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Antonella Tinari
4Center for Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
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Martina Borghi
5Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Martina Borghi
Andrea Canitano
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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Paul F. McKay
2Imperial College London, Department of Infectious Disease, Norfolk Place, London, UK
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Roberta Bona
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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Maria Fenicia Vescio
5Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Maria Fenicia Vescio
Felicia Grasso
5Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Felicia Grasso
Maria Blasi
6Department of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, USA
7Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
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Silvia Baroncelli
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Silvia Baroncelli
Gabriella Scarlatti
8Viral Evolution and Transmission Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
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Celia LaBranche
9Department of Surgery, Duke University School of Medicine, Durham, NC, USA
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David Montefiori
9Department of Surgery, Duke University School of Medicine, Durham, NC, USA
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Mary E. Klotman
6Department of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, USA
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Rogier W. Sanders
10Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, the Netherlands
11Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, USA
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Robin J. Shattock
2Imperial College London, Department of Infectious Disease, Norfolk Place, London, UK
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Donatella Negri
5Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
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Andrea Cara
1National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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  • ORCID record for Andrea Cara
  • For correspondence: andrea.cara@iss.it
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ABSTRACT

Integrase Defective Lentiviral Vectors (IDLVs) represent an attractive vaccine platform for delivering HIV-1 antigens, given their ability to induce specific and persistent immune responses in both mice and non-human primates (NHPs). Recent advances in HIV-1 immunogen design demonstrated that native-like HIV-1 Envelope (Env) trimers that mimic the structure of virion-associated Env induce neutralization breadth in rabbits and macaques. Here, we describe the development of an IDLV-based HIV-1 vaccine expressing either soluble ConSOSL.UFO.664 or membrane-tethered ConSOSL.UFO.750 native-like Env immunogens with enhanced bNAb epitopes exposure. We show that IDLV can be pseudotyped with properly folded membrane-tethered native-like UFO.750 trimers. After a single IDLV injection in BALB/c mice, IDLV-UFO.750 induced a faster humoral kinetic as well as higher levels of anti-Env IgG compared to IDLV-UFO.664. IDLV-UFO.750 vaccinated cynomolgus macaques developed unusually long-lasting anti-Env IgG antibodies, as underlined by their remarkable half-life both after priming and boost with IDLV. After boosting with recombinant ConM SOSIP.v7 protein, two animals developed neutralization activity against the autologous tier 1B ConS virus mediated by V1/V2 and V3 glycan sites responses. By combining the possibility to display stabilized trimeric Env on the vector particles with the ability to induce sustained humoral responses, IDLVs represent an appropriate strategy for delivering rationally designed antigens to progress towards an effective HIV-1 vaccine.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 09, 2021.
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Persistent Immunogenicity of Integrase Defective Lentiviral Vectors delivering membrane tethered Native-Like HIV-1 Envelope Trimers
Alessandra Gallinaro, Maria Franca Pirillo, Yoann Aldon, Serena Cecchetti, Zuleika Michelini, Antonella Tinari, Martina Borghi, Andrea Canitano, Paul F. McKay, Roberta Bona, Maria Fenicia Vescio, Felicia Grasso, Maria Blasi, Silvia Baroncelli, Gabriella Scarlatti, Celia LaBranche, David Montefiori, Mary E. Klotman, Rogier W. Sanders, Robin J. Shattock, Donatella Negri, Andrea Cara
bioRxiv 2021.10.08.462761; doi: https://doi.org/10.1101/2021.10.08.462761
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Persistent Immunogenicity of Integrase Defective Lentiviral Vectors delivering membrane tethered Native-Like HIV-1 Envelope Trimers
Alessandra Gallinaro, Maria Franca Pirillo, Yoann Aldon, Serena Cecchetti, Zuleika Michelini, Antonella Tinari, Martina Borghi, Andrea Canitano, Paul F. McKay, Roberta Bona, Maria Fenicia Vescio, Felicia Grasso, Maria Blasi, Silvia Baroncelli, Gabriella Scarlatti, Celia LaBranche, David Montefiori, Mary E. Klotman, Rogier W. Sanders, Robin J. Shattock, Donatella Negri, Andrea Cara
bioRxiv 2021.10.08.462761; doi: https://doi.org/10.1101/2021.10.08.462761

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