Resumen
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-oleoylphosp ...»»»»
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.^^^^
Citación Bibliográfica:
Molinos-Albert, L., Bilbao, Eneritz, Agulló, Luis, Marfil, Silvia, García, Elisabet, Rodríguez de la Concepción, Maria Luisa, Izquierdo-Useros, Nuria, Vilaplana, Cristina, Contreras, F. Xabier, Floor, Martin, Cardona, Pere J., Martinez-Picado, Javier Clotet, Bonaventura Villà-Freixa, Jordi Lorizate, Maier Carrillo, Jorge Blanco Julià.. (2017). Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif. Scientific Reports., 7(40800)