Generation of a Nonbilayer Lipid Nanoenvironment after Epitope Binding Potentiates Neutralizing HIV-1 MPER Antibody.

Establishment of interactions with the envelope lipids is a cardinal feature of broadly neutralizing antibodies (bnAbs) that recognize the Env membrane-proximal external region (MPER) of HIV. The lipid envelope constitutes a relevant component of the full "quinary" MPER epitope, and thus antibodies may be optimized through engineering their capacity to interact with lipids. However, the role of the chemically complex lipid nanoenvironment in the mechanism of MPER molecular recognition and viral neutralization remains poorly understood.

Functional Delineation of a Protein-Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8.

Antibody engagement with the membrane-proximal external region (MPER) of the envelope glycoprotein (Env) of HIV-1 constitutes a distinctive molecular recognition phenomenon, the full appreciation of which is crucial for understanding the mechanisms that underlie the broad neutralization of the virus. Recognition of the HIV-1 Env antigen seems to depend on two specific features developed by antibodies with MPER specificity: (i) a large cavity at the antigen-binding site that holds the epitope amphipathic helix; and (ii) a membrane-accommodating Fab surface that engages with viral phospholipids. Thus, besides the main Fab-peptide interaction, molecular recognition of MPER depends on semi-specific (electrostatic and hydrophobic) interactions with membranes and, reportedly, on specific binding to the phospholipid head groups.