Immunogenicity of Membrane-bound HIV-1 gp41 Membrane-proximal External Region (MPER) Segments Is Dominated by Residue Accessibility and Modulated by Stereochemistry

Abstract

Background: Despite analyses of broadly neutralizing anti-HIV-1 antibodies directed against the gp41 MPER segment, there exists a paucity of structural information on MPER immunogenicity. Results: Immunodominance of Trp-680 in the MPER arrayed on liposomes is modified by membrane anchoring. Conclusion: Immunogenicity is manipulatable through subtle structural modification. Significance: Learning about the structural basis of immunogenicity is critical for eliciting desired B cell antibody production through vaccination.

Thermodynamic Analysis of the Binding of 2F5 (Fab and Immunoglobulin G Forms) to Its gp41 Epitope Reveals a Strong Influence of the Immunoglobulin Fc Region on Affinity

“…Additional hydrophobic contacts between the long CDRH3 loop of 2F5 and residues downstream into the MPER C terminus have been proposed to help stabilize the extended loop-bound conformation (16,34). The CDRH3 loop has also been reported recently to assist in the extraction of the lipid-immersed MPER prior to tight binding (12)(13)(14). Because the MPER peptides adopt an ␣-helical conformation in a membrane environment (35), the conformational change needed for 2F5 binding should imply an additional energy cost.…”

“…The atomic interactions of the complex between the core epitope and antibody 2F5 have been described in detail (8 -10). An additional complexity of the 2F5 epitope has been suggested, including other gp41 regions (11) and an influence of the proximal lipid bilayer (12,13), which strongly affects its immunogenicity (14). Understanding the interaction of this antibody with its epitope requires not only a detailed knowledge of the structure but also knowing the physicochemical characteristics of the antigen (Ag)-antibody complex described by the kinetic rate constants, equilibrium constants, and thermodynamics of binding.…”

Toward increased concentration sensitivity for continuous wave EPR investigations of spin-labeled biological macromolecules at high fields

“…Structure and structure-function relationships of macromolecules are areas of intense EPR effort [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Coupled with site-directed spin-labeling (SDSL), EPR is oftentimes used to characterize protein and nucleic acid structures and dynamics, conformational changes, molecule folding, macromolecule complexes, and oligomeric structures [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]17].…”

“…Coupled with site-directed spin-labeling (SDSL), EPR is oftentimes used to characterize protein and nucleic acid structures and dynamics, conformational changes, molecule folding, macromolecule complexes, and oligomeric structures [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]17]. The majority of biomolecules do not contain unpaired electrons from which one can obtain an EPR signal; therefore, spin-labeling approaches have been developed [15,[18][19][20][21][22][23][24][25] where site-specific persistent radicals or paramagnetic metal-probes are incorporated at specific locations within a biomolecule.…”

Anti-MPER Antibodies with Heterogeneous Neutralization Capacity Are Detectable in Most Untreated HIV Infected Individuals

“…The ability of the human immune system to mount a neutralizing response against this region and their protective activity in animal models [5] made the MPER a promising target for vaccine design aiming to develop a protective neutralizing response against HIV-1 [6][7][8]. However, the elicitation of such neutralizing responses against the MPER is challenging likely because of its poor immunogenicity due to topological constraints or to the existence of immunodominant nonneutralizing regions within gp41 [7,9,10]. Furthermore, some of the features presented by both 2F5 and 4E10 antibodies including lipid recognition and autoreactivity, represent a considerable immunological barrier when designing immunogens aiming to mimic anti-MPER responses [11][12][13].…”