Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies  Peter D. Kwong, John R. Mascola  Immunity  Volume 37, Issue 3, Pages 412-425 (September 2012) DOI: 10.1016/j.immuni.2012.08.012 Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 1 HIV-1 Spike and Its Recognition by Neutralizing Antibodies The ∼20 Å cryoelectron tomogram of the HIV-1 BaL isolate viral spike (Liu et al., 2008) is shown in gray, fitted with three copies of the HIV-1 gp120 core in the CD4-bound conformation (Pancera et al., 2010a), with modeled glycans and with modeled sites of Env vulnerability colored red (CD4-binding site), green (glycan N160 in V1/V2), blue (glycan N332 at the base of V3), and cyan (MPER of gp41). Effective mAbs are shown that recognize each site (see main text for fuller descriptions and references). Movie S1 available online shows the viral spike and recognizing antibodies. Immunity 2012 37, 412-425DOI: (10.1016/j.immuni.2012.08.012) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 2 B Cell Ontogenies of Broadly Neutralizing Antibodies Effective neutralizing human antibodies have unusual features, a result of unusual recombination, somatic mutation, or both. CD4-binding site antibodies, represented here by VRC01, are described in the top row. A number of effective neutralizers use mimicry of CD4 by their heavy chain to effect near pan-neutralization. All of these derive from similar VH genes, VH1-2 or VH1-46, but otherwise display a variety of CDR H3 lengths and VK or VL partners. Next-generation sequencing and systems-level bioinformatics allow specific CDR H3 lineages to be traced to identify thousands of clonal variants. For VRC01, only the more highly somatically matured antibodies are capable of neutralizing HIV-1. V1V2-directed antibodies, represented here by PG9, are described in the second row. All V1V2-directed broadly neutralizing antibodies identified to date display unusually long CDR H3s. These are likely required to penetrate the glycan shield to reach conserved features of Env-protein surface. For PG9, recombination that generates a 28 amino acid CDR H3 appears to occur as an early event, with somatic mutation fine tuning glycan recognition. Glycan-V3-directed antibodies, represented here by PGT128, are described in the third row. Antibodies directed toward this site are highly diverse. Some, such as PGT128, have CDR H3s that are not so unusual but display high degrees of somatic mutation. MPER-directed antibodies, represented here by 10E8, are described in the bottom row. These gp41-directed neutralizers are quite diverse, with some such as 2F5, Z13, and 4E10 requiring significant degrees of β strand interactions, whereas 10E8 interacts entirely through its CDR loops. Despite this diversity, all show moderately long CDR H3s and unusual degrees of somatic mutation. Immunity 2012 37, 412-425DOI: (10.1016/j.immuni.2012.08.012) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 3 Broadly Neutralizing Immunity to HIV-1 Infection by HIV-1 (top panel) generates broadly neutralizing antibodies after 2 or more years of infection in ∼20% of individuals. Next-generation sequencing of antibody-gene transcripts from memory B cells coupled with bioinformatics analyses of the resulting antibodyomes provides the potential to follow the development of effective neutralizing antibodies during natural infection. HIV-1-neutralizing mAbs can potentially be used in passive modes of protection (far right arrow connecting top and bottom panels), either singly or in combination. Based upon our understanding of the B cell ontogenies of broadly neutralizing antibodies, immunogens can potentially be developed to re-create the elicitation of effective mAb neutralizers (bottom panel). Immunity 2012 37, 412-425DOI: (10.1016/j.immuni.2012.08.012) Copyright © 2012 Elsevier Inc. Terms and Conditions