Abstract
M36 is the first member of a novel class of potent HIV-1 entry inhibitors based on human engineered antibody domains (eAds). It exhibits broad inhibitory activity suggesting that its CD4-induced epitope is highly conserved. Here, we describe fine mapping of its epitope by using several approaches. First, a panel of mimotopes was affinity-selected from a random peptide library and potential m36-binding residues were computationally predicted. Second, homology modeling of m36 and molecular docking of m36 onto gp120 revealed potentially important residues in gp120-m36 interactions. Third, the predicted contact residues were verified by site-directed mutagenesis. Taken together, m36 epitope comprising three discontinuous sites including six key gp120 residues (Site C1: Thr123 and Pro124; Site C3: Glu370 and Ile371; Site C4: Met426 and Trp427) were identified. In the 3D structure of gp120, the sites C1 and C4 are located in the bridging sheet and the site C3 is within the β15-α3 excursion, which play essential roles for the receptor- and coreceptor-binding and are major targets of neutralizing antibodies. Based on these results we propose a precise localization of the m36 epitope and suggest a mechanism of its broad inhibitory activity which could help in the development of novel HIV-1 therapeutics based on eAds.
Highlights
The epidemic of HIV-1 infection continues to be an unabated worldwide problem in the absence of an effective vaccine
These antibodies include VRC01 and VRC02 [10], which target the CD4-binding site (CD4bs), PG9 and PG16 [11], which are directed against the conserved regions of variable loops of gp120 preferentially expressed on trimeric envelope glycoproteins (Envs), the series of PGT antibodies [12], which bind to various novel epitopes on gp120, and 10E8, which is specific for the membrane-proximal external region (MPER) of gp41
This work was aimed at mapping the fine epitope of m36, a highly potent human antibody domain-based inhibitor of HIV-1 entry targeting the gp120 of HIV-1 Env
Summary
The epidemic of HIV-1 infection continues to be an unabated worldwide problem in the absence of an effective vaccine. Since 2009, new human broadly nAbs against HIV-1 have been identified by using novel selection approaches such as high-throughput B cell sorting and functional screening These antibodies include VRC01 and VRC02 [10], which target the CD4-binding site (CD4bs), PG9 and PG16 [11], which are directed against the conserved regions of variable loops of gp120 preferentially expressed on trimeric Envs, the series of PGT antibodies [12], which bind to various novel epitopes on gp120, and 10E8, which is specific for the membrane-proximal external region (MPER) of gp. There are not much data from in vivo experiments that could prove this possibility
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