A lack of neutralizing antibodies distinguishes HIV-1 from most other viral pathogens and is responsible to a large degree for the ability of HIV-1 to maintain a persistent infection. We have used X-ray crystallography to investigate the epitopes of broadly neutralizing antibodies and their mechanisms of neutralization. We have also used next-generation sequencing of B cell transcripts to understand the developmental processes by which broadly neutralizing antibodies mature. In particular we have focused on CD4-binding site antibodies like VRC01, V1V2-directed antibodies like PG9 and CAP256-VRC26, membrane-proximal antibodies like 2F5 and 10E8, and gp120-gp41 reactive antibodies like 35O22. Of particular interest for vaccine design are reproducible antibodies, those antibodies which have similar modes of recognition and similar B cell ontogenies in multiple donors, as such antibodies might be induced in the general population with a common set of immunogens. We have recently focused on three classes of such antibodies, those of the VRC01 class, which derive from the VH1-2 germline gene, those of the 8ANC131 class, which derive from the VH1-46 germline gene, and those targeted against the V1V2, which have a protruding anionic loop formed by recombination that interacts with strand C in a strand-strand manner.
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