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    • As a result the gp V

    2018-10-25

    As a result, the gp120 V1V2 region has been of intense interest owing to its immunogenic promise; however, V1V2 has proven difficult to characterize structurally. V1V2 has been observed in crystal structures in a variety of conformations. Bound to ache inhibitor CH58 and CH59 isolated from RV144 vaccinees, V2 peptides demonstrated helix and loop-helix conformations respectively (Liao et al., 2013). When presented in the context of a scaffold, the antibody-bound V1V2 has adopted stranded conformations, notable not only because of the differing conformation but also because some of these antibodies were broadly neutralizing (McLellan et al., 2011; Pancera et al., 2013). The stranded V2 conformation was recapitulated in pre-fusion Env trimer structures (Julien et al., 2013; Pancera et al., 2014); however, the predominant responses to it as an antigen have been with glycan V3 antibodies (Pancera et al., 2014). Thus interest remains in directing an immune response against V1V2. The V2 antibody CH58 has been biochemically and immunologically characterized (Liao et al., 2013). CH58 mediates ADCC against tier 2 virus-infected CD4+ T cell targets (Haynes et al., 2012), has a footprint at a site of immune pressure (gp120 Lys169) (Rolland et al., 2012), and like PG9 and CH01 (Liao et al., 2013; McLellan et al., 2011) binds the gp120 V2 region involving Lys169. CH58 cross-blocks binding of PG9 and CH01 V1V2 broadly neutralizing antibodies (bNAbs) to Env, but CH58 does not have bnAb activity and only neutralized the tier 1 HIV-1 CRF_01 AE strain 92TH023 that was included in ALVAC as a prime vaccine immunogen (Liao et al., 2013; McLellan et al., 2011; Rerks-Ngarm et al., 2009; Walker et al., 2009). Importantly, the germline precursor to CH58 has been inferred and shows a relatively low number of mutations leading to its functions: only 11 mutations occurred from germline to mature antibody in both light and heavy (Fab component) chains (Liao et al., 2013). Furthermore, CH58 has been found to bear a key Glu–Asp (ED) pair in its second light chain complementarity determining region (LCDR2) (Liao et al., 2013) that is conserved among humans and rhesus macaques (Wiehe et al., in press). This ED motif is predominantly present in V2 antibodies where the negatively charged Glu and Asp side chains may form salt bridges with the positively charged Lys and Arg side chains prevalent in variants of the V2 sequence when presented as a linear epitope such as CH59, HG107, and HG120 (Liao et al., 2013; Wiehe et al., in press). Moreover, the presence of this ED motif within the preconformed LCDR2 suggests a pathway in which germline antibodies bearing it can recognize basic residues within V2 (North et al., 2011; Wiehe et al., in press). The relatively low number of mutations between the inferred, unmutated ancestor of CH58 (CH58-UA) and the mature CH58 suggested this relationship as ripe for study in the area of antibody lineages. In terms of structure, it has been established that germline precursors tend to display greater flexibility in their idiotopes than mature antibodies, the rationale being that evolution tends to favor greater diversity in immune responses so that it can react to new threats (Foote and Milstein, 1994). Even through the maturation process, mature antibodies can exist in an equilibrium of two or more structural isomers, only one of which is the binding conformer; stated differently, mutations that accumulate during antibody maturation can work cooperatively to narrow conformational ensembles (Foote and Milstein, 1994; Manivel et al., 2000; Zimmermann et al., 2006). In support of the notion of promiscuous germline antibodies, it has been specifically found that germline antibodies have HCDR3 sequences capable of adopting a wide range of conformations (Babor and Kortemme, 2009). However, this cannot be taken to mean that mutations impacting immunogenicity must necessarily occur within CDRs. In fact mutations that impact functionality have been shown to occur in any of the CDRs as well as in the IgG framework regions (Fera et al., 2014; Klein et al., 2013). Recently, it has been demonstrated that antibody paratopes with CDRs preconfigured (rigidified) through the maturation process are likely to experience large affinity gains through maturation (Schmidt et al., 2013). The mechanism for that particular study (the CH65-67 lineage of influenza HA antibodies) was rigidification of the antibody paratope through key somatic mutations at the HCDR3 anchorpoints (Schmidt et al., 2013).