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

• Published in: Scientific reports Vol. 7; no. 1; p. 40800
• Main Authors: Molinos-Albert, Luis M., Bilbao, Eneritz, Agulló, Luis, Marfil, Silvia, García, Elisabet, Rodríguez de la Concepción, Maria Luisa, Izquierdo-Useros, Nuria, Vilaplana, Cristina, Nieto-Garai, Jon A., Contreras, F.-Xabier, Floor, Martin, Cardona, Pere J., Martinez-Picado, Javier, Clotet, Bonaventura, Villà-Freixa, Jordi, Lorizate, Maier, Carrillo, Jorge, Blanco, Julià
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.01.2017; Nature Publishing Group
• Subjects: 631/250/255/1901; 631/250/590/2291; 82/1; 82/16; 82/75; 82/80; 82/83; Animals; Antibodies; Antigens; Cholesterol; Epitopes; Epitopes - chemistry; Epitopes - immunology; Female; Glycoprotein gp41; HIV Envelope Protein gp41 - chemistry; HIV Envelope Protein gp41 - immunology; Humanities and Social Sciences; Immunization; Immunodominance; Immunogenicity; Immunogenicity, Vaccine; Immunoglobulin G; Lipid A; Lipids; Liposomes; Major histocompatibility complex; Membrane Lipids - chemistry; Membrane Lipids - metabolism; Mice; Mice, Inbred C57BL; Monophosphoryl lipid A; multidisciplinary; Peptides - chemistry; Peptides - immunology; Phosphatidylserine; Science; Science (multidisciplinary); Sphingomyelin; Tetanus; Tetanus Toxoid - chemistry; Tetanus Toxoid - immunology; TLR4 protein; Toll-like receptors; Vaccines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep40800

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.