Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies

Abstract

Antibodies that neutralize diverse strains of HIV-1 develop in ∼20% of HIV-1-infected individuals, and isolation and structural characterization of these antibodies are revealing how they recognize the envelope glycoprotein spike. Broadly reactive neutralizing antibodies utilize just a few sites of spike vulnerability and converge on select modes of recognition. These antibodies have unusual features: uncommonly long complementarity-determining loops, extensive somatic mutation, or both. Recent advances in next-generation sequencing of antibody-gene transcripts are providing genetic records of the development of neutralizing antibodies. These records inform an understanding of the naive B cell repertoire, of somatic mutation, and of the resulting antibody features that are critical to effective HIV-1 neutralization; based on these, we propose an ontogeny and structure-based system of antibody classification. The human immune system is capable of developing antibodies that broadly neutralize HIV-1--and an increasingly detailed view is accumulating for how effective immunity against HIV-1 can be generated.

Figure 1. HIV-1 spike and its recognition by neutralizing antibodies

The ~20 Å cryo-electron tomogram of the HIV-1 BaL isolate viral spike (Liu et al., 2008) is shown in grey, fitted with three copies of 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 base of V3) and cyan (MPER of gp41). Effective mAbs are shown that recognize each site (see main text for fuller descriptions and references). A movie of the viral spike and of recognizing antibodies can be viewed.

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. A number of effective neutralizers use mimicry of CD4 by their heavy chain to affect near-pan-neutralization. All of these derive from similar V_H genes, VH1-2 or VH1-46, but otherwise display a variety of CDR H3 lengths and Vκ or Vλ partners. Deep 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 affinity matured antibodies are capable of neutralizing HIV-1. V1V2-directed antibodies, represented here by PG9. 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 29-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. Antibodies directed towards 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. These gp41-directed neutralizers are quite diverse, with some such as 2F5, Z13 and 4E10 requiring significant degrees of β-strand interactions, while 10E8 interacts entirely through its CDR loops. Despite this diversity, all show moderately long CDR H3s and unusual degrees of somatic mutation.

Figure 3. Broadly neutralizing immunity to HIV-1

Infection by HIV-1 (top panel) generates broadly neutralizing antibodies after two or more years of infection in ~20% of individuals. Deep 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 upper and lower 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).