Abstract
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.
Highlights
The HIV-1 envelope glycoprotein (Env) is a trimer of heterodimers composed by the non-covalent association of gp[120] and gp[41] subunits[1]
The isolation of broadly neutralizing antibodies from these individuals identified several antigenic vulnerability sites within Env including the CD4 binding site[4,7,8,9,10]; glycan-dependent epitopes defined by residues N160 and N332 in the V1/V2 and V3 gp[120] loops respectively[10,11,12]; the gp[41] Membrane Proximal External Region (MPER)[13,14,15,16]; and recently discovered regions including residues from both gp[120] and gp4117–19 and the gp[41] fusion peptide[20]
We tested phosphatidylserine (PS) that binds to different receptors on the surface of phagocytic cells[39,40], and the ganglioside GM3, which binds to CD169 (SIGLEC-1) on the membrane of subcapsular sinus macrophages[41,42], a highly specialized antigen presenting cell population that play a pivotal role during the induction of the humoral response[43]
Summary
The HIV-1 envelope glycoprotein (Env) is a trimer of heterodimers composed by the non-covalent association of gp[120] and gp[41] subunits[1]. The isolation of broadly neutralizing antibodies (bNAbs) from these individuals identified several antigenic vulnerability sites within Env including the CD4 binding site[4,7,8,9,10]; glycan-dependent epitopes defined by residues N160 and N332 in the V1/V2 and V3 gp[120] loops respectively[10,11,12]; the gp[41] Membrane Proximal External Region (MPER)[13,14,15,16]; and recently discovered regions including residues from both gp[120] and gp4117–19 and the gp[41] fusion peptide[20] The study of these regions has guided efforts in HIV-1 vaccine development during the last years[21,22]. Regardless of the lipid composition used, the response targeted an epitope overlapping the 2F5-binding motif, revealing the existence of a gp[41] immunodominant region that cannot be bypassed by any lipid mixture
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