Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design. •VLPs and stabilized Env trimers identify HIV-1-neutralizing N90-VRC38 Ab lineage•Co-crystal structure of Ab N90-VRC38.01 with scaffolded V1V2-Env apex•N90-VRC38 lineage targets the apex of HIV-1 Env trimer with non-protruding loops•New mechanism of Ab:trimer-apex binding informs V1V2 vaccine strategies To date, long recognition loops have been a hallmark of apex-targeting antibodies. Cale et al. identify a lineage of HIV-1-neutralizing antibodies that target the envelope trimer apex. The N90-VRC38 lineage uses a loop of average length—a feature that may make it a useful prototype for vaccine design.