Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif

The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated...

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Detalles Bibliográficos
Autores: Molinos-Albert, Luis M., Bilbao, Eneritz, Agulló, Luis, Marfil, Sílvia, García, Elisabet, Rodríguez de la Concepción, Maria L., Izquierdo Useros, Nuria, Vilaplana, Cristina, Nieto-Garai, Jon A., Contreras, F. Xabier, Floor Pilquil, Martin Luciano, Cardona, Pere J., Martinez Picado, Francisco Javier, Clotet, Bonaventura, Villà-Freixa, Jordi, Lorizate, M., Carrillo, Jorge, Blanco, Julià
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:UVic-UCC
Repositorio:RiUVic. Repositori institucional de la UVic-UCC
OAI Identifier:oai:dspace.uvic.cat:10854/4867
Acceso en línea:http://hdl.handle.net/10854/4867
https://doi.org/10.1038/srep40800
Access Level:acceso abierto
Palabra clave:Sida -- Tractament
VIH (Virus)
Descripción
Sumario:The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.

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