Persistent immunogenicity of integrase defective lentiviral vectors delivering membrane-tethered native-like HIV-1 envelope trimers

Author:

Gallinaro Alessandra,Pirillo Maria Franca,Aldon YoannORCID,Cecchetti Serena,Michelini Zuleika,Tinari AntonellaORCID,Borghi Martina,Canitano Andrea,McKay Paul F.ORCID,Bona Roberta,Vescio Maria FeniciaORCID,Grasso Felicia,Blasi MariaORCID,Baroncelli SilviaORCID,Scarlatti GabriellaORCID,LaBranche CeliaORCID,Montefiori David,Klotman Mary E.ORCID,Sanders Rogier W.ORCID,Shattock Robin J.ORCID,Negri Donatella,Cara AndreaORCID

Abstract

AbstractIntegrase 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.

Funder

EC | EC Seventh Framework Programm | FP7 Health

Fondation Dormeur, Vaduz

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

EC | Horizon 2020 Framework Programme

Publisher

Springer Science and Business Media LLC

Subject

Pharmacology (medical),Infectious Diseases,Pharmacology,Immunology

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