2G12-Expressing B Cell Lines May Aid in HIV Carbohydrate Vaccine Design Strategies

Abstract

The highly conserved cluster of high-mannose glycans on the HIV-1 envelope glycoprotein, gp120, has been highlighted as a target for neutralizing antibodies. 2G12, the first HIV-1 antiglycan neutralizing antibody described, binds with an unusual domainexchanged structure that creates a high-affinity multivalent binding surface. It is an interesting challenge for rational vaccine design to generate immunogens capable of eliciting domain-exchanged 2G12-like responses. We recently showed that di-mannose recognition by the variable domains of 2G12 is independent of domain exchange but that exchange is critical for virus neu-

Diverse Recombinant HIV-1 Envs Fail To Activate B Cells Expressing the Germline B Cell Receptors of the Broadly Neutralizing Anti-HIV-1 Antibodies PG9 and 447-52D

“…Although most germline antibody-Env interactions have focused on anti-CD4-BS antibodies, a few studies examined similar interactions between Env and bNMAbs that recognize epitopes outside the CD4-BS. Doores et al reported that the germline form of bnMAb 2G12 (a carbohydrate-binding antibody derived from VH3-21) does not recognize Env (35). In contrast, Bonsignori et al examined the interaction of CH01 to CH04, antibodies that recognize a complex epitope involving elements of the second and third variable regions (V2 and V3 loops) of the gp120 subunit, including an N-linked glycan at position 160, and reported that a very limited number of Envs bind the predicted germline form of this Ab (14).…”

Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions

“…Effective immunogens must, therefore, be capable of engaging the B cell receptor (i.e., the gl-bnAb), before affinity maturation of the bnAb in the germinal centers. However, this process is hampered by the low affinity of gl-bnAbs to Env, often due to their inability to accommodate conserved N-linked glycans ( Doores et al., 2013 , Hoot et al., 2013 , Ma et al., 2011 , McGuire et al., 2014 , Xiao et al., 2009 ). Thus an alternative, albeit closely linked, approach to eliciting bnAbs, is to prime with glycan-depleted immunogens capable of engaging gl-bnAbs, and subsequently boost with their “filled-in” derivatives to drive the development of neutralization breadth ( Jardine et al., 2013 , McGuire et al., 2013 , Medina-Ramirez et al., 2017 , Stamatatos et al., 2017 , Steichen et al., 2016 ).…”

Synthesis of a Pentasaccharide Fragment Related to the Inner Core Region of Rhizobial and Agrobacterial Lipopolysaccharides

“… 10 , 11 Of note is the structural resemblance of the α-(1 → 2)-linked oligomannose part to the D1 arm of mammalian high-mannose glycans, which are particularly abundant on HIV-1 gp120. 12 Rhizobium radiobacter Rv3 LOS and heat-killed cells are bound by the oligomannose-specific HIV-neutralizing antibody 2G12 and a crystal structure of the carbohydrate backbone of Rhizobium radiobacter strain Rv3 complexed to the 2G12 antibody has recently been determined. 13 In order to further exploit the natural mimicry of high-mannose carbohydrate epitopes of HIV-1 gp120 seen with this bacterial LOS scaffold, we have set out to extend the bacterial oligosaccharides in order to elicit HIV neutralizing antibodies.…”