V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity

Abstract

SUMMARY Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228–3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5–51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3–21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens.

AAV-Mediated Expression of Broadly Neutralizing and Vaccine-like Antibodies Targeting the HIV-1 Envelope V2 Region

“…They are similar to V1V2 antibodies, which correlated with a reduced risk of HIV-1 infection and may have contributed to protection in the RV144 vaccine trial 18, 19. CAP228 antibodies have also been shown to mediate the ADCC of infected cells 39 . Sequences encoding VRC01 40 and PGT121, 13 which target the CD4bs and V3 glycan, respectively, were used in previous VIP studies30, 31, 41 and included here as controls.

Figure 1Selected Antibodies and the Optimized Antibody Expression Cassette(A) Antibodies from the CAPRISA cohort used for packaging into AAVs.

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“…The CAP228 antibodies recognize a different conformation of V2 not present on the trimeric envelope, and they are, therefore, not broadly neutralizing 57 . However, these antibodies mediate ADCC 39 and are similar to antibodies associated with moderate efficacy in the RV144 trial. A major limitation of this vaccine regimen is that antibody responses are not durable and wane after 12 months, requiring re-boosting.…”

Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses

“…Several cross-clade-reactive human mAbs targeting the V1V2 region on the Env spike have been isolated and extensively characterized (Haynes and Mascola, 2017; Li et al, 2015). For example, the V2p epitope family is defined by human mAbs CH58 and CH59, isolated from an RV144 vaccinee (Liao et al, 2013), and CAP228–16H, isolated from an HIV+ individual (van Eeden et al, 2018; Wibmer et al, 2018). These mAbs react with V2 peptides, which are structurally unconstrained and preferentially assume a helical or helical coil structure (Liao et al, 2013).…”

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

“…Therefore, focus in the viral antibody field is often directed towards development of broadly-neutralizing antibodies against which it is difficult for viruses to create escape mutants [18]. In this relation, human immunodeficiency virus (HIV) has in particular been a challenging indication, although researchers have recently reported promising results on the generation of broadly-neutralizing efficacious monoclonal antibodies targeting key epitopes on glycoproteins on the HIV particle [19][20][21][22]. Another challenge with viral pathogens is that it can be difficult to predict in vivo efficacy for therapeutic monoclonal antibodies targeting the virus, as in vitro efficacy is not always predictable due to the complex pathogenesis involved in viral infections.…”