Abstract
Antibodies against the Membrane-Proximal External Region (MPER) of the Env gp41 subunit neutralize HIV-1 with exceptional breadth and potency. Due to the lack of knowledge on the MPER native structure and accessibility, different and exclusive models have been proposed for the molecular mechanism of MPER recognition by broadly neutralizing antibodies. Here, accessibility of antibodies to the native Env MPER on single virions has been addressed through STED microscopy. STED imaging of fluorescently labeled Fabs reveals a common pattern of native Env recognition for HIV-1 antibodies targeting MPER or the surface subunit gp120. In the case of anti-MPER antibodies, the process evolves with extra contribution of interactions with the viral lipid membrane to binding specificity. Our data provide biophysical insights into the recognition of the potent and broadly neutralizing MPER epitope on HIV virions, and as such is of importance for the design of therapeutic interventions.
Highlights
Antibodies against the Membrane-Proximal External Region (MPER) of the envelope glycoprotein (Env) gp[41] subunit neutralize human immunodeficiency virus type-1 (HIV-1) with exceptional breadth and potency
A mechanistic understanding of MPER recognition by broadly neutralizing antibodies (bnAbs) has been hampered by the limited information available on its native antigenic structure: a molecular surface that lies in contact with the viral membrane at the base of the Env complex (Fig. 1)
To analyze MPER accessibility through stimulated emission depletion (STED) microscopy in the native Env complex, 10E8 and 4E10 Fabs were conjugated with the fluorescent probe Abberior STAR RED
Summary
Antibodies against the Membrane-Proximal External Region (MPER) of the Env gp[41] subunit neutralize HIV-1 with exceptional breadth and potency. A mechanistic understanding of MPER recognition by bnAbs has been hampered by the limited information available on its native antigenic structure: a molecular surface that lies in contact with the viral membrane at the base of the Env complex (Fig. 1). This structural complexity has proven challenging to reproduce by model systems amenable to biophysical and biochemical characterization, and precludes crystallization of MPER-containing Env specimens[8,12,13,14]. Vulnerability sites V1/V2 CD4bs MPER enable purification, which does not provide an opportunity to understand the native MPER epitope unliganded, and the mechanism of recognition; it only provides a still view postbinding albeit with sub-nanometer details
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