Broad neutralization coverage of HIV by multiple highly potent antibodies

Abstract

Broadly neutralizing antibodies (bnAbs) against highly variable viral pathogens are much sought-after to treat or protect against global circulating viruses. We have probed the neutralizing antibody repertoires of four HIV-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies (MAbs) that neutralize broadly across clades. Many of the new MAbs are almost 10-fold more potent than the recently described PG9, PG16, and VRC01 bnMAbs and 100-fold more potent than the original prototype HIV bnMAbs1–3. The MAbs largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV bnMAbs now available reveals that certain combinations of antibodies provide significantly more favorable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV bnMAbs, from several donors, that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…The V3-glycan PCDN, BF520-derived and DH270 bnAb lineages share some common traits: 1) differently from previously described V3-gylcan bnAbs (23, 25), their evolution did not involve insertion/deletion (indel) events, demonstrating that indels are not a universal requirement for the V3-glycan bnAb class to acquire neutralization breadth; 2) neutralization breadth was acquired with relatively modest levels of somatic hypermutation that can be achieved through vaccination (57, 60, 61), and 3) the UCA of the V3-glycan lineages did not neutralize or bind autologous TF suggesting the hypothesis that V3-glycan bnAb lineages may arise in response to altered forms of the Env protein.…”

Identification and specificity of broadly neutralizing antibodies against HIV

“…The glycan site at residue 160 is typically critical for these bnAbs and a decrease in neutralization is seen when additional glycan sites are removed from the V1, V2, and V3 loops in a viral isolate‐dependent manner 66. With the isolation of additional N160‐dependent apex bnAbs, by our group and others,22, 42, 51, 67 this class can be divided into four groups typified by the prototypes PG9, CH01, PGT145, and CAP256.VRC26.09 (CAP256.09) 68. All four prototypes bind N160 and basic residues in the lysine‐rich strand C of the V2 loop, but the exact residues required for each epitope vary, with a lysine at position 169 the most commonly shared feature 68.…”

“…Subsequently, advances in the production of soluble near‐native stabilized Env trimers46 have allowed better selection of Env‐specific B cells, excluding those which bind regions not exposed on the infectious viral spike. Using this method, we isolated PGDM140028 from the same donor that previously yielded the PGT141–145 family of bnAbs via the B‐cell culturing approach 22. Furthermore, stabilized BG505 SOSIP.664 trimers have been used as baits to isolate two bnAbs which occupy overlapping epitopes at the gp120‐gp41 interface and also contact the fusion peptide, ACS20247 and VRC34 48.…”

“…By comparing structural information generated for different families within this class, it was shown that the N332/GDIR epitope is accessed from a variety of angles by the different bnAbs, which use diverse binding modes, leading to its definition as a supersite of vulnerability 71. Furthermore, in contrast to some other bnAb classes, these high‐mannose patch bnAbs use a variety of V, D, and J germline genes and do not appear to share particular genetic traits required for binding this epitope 22, 71. Thus, it would be difficult to use an NGS approach to identify bnAbs from new donors even if the serum neutralization was clearly N332 dependent.…”

“…High‐throughput neutralization assays were a major factor in changing that situation. The ability to analyze mAb and serum activity against large panels of viruses was demonstrated20 and subsequently used to evaluate large numbers of HIV‐infected donors in the International AIDS Vaccine Initiative (IAVI) Protocol G and C studies to identify those with exceptionally potent and broad sera,8 map the specificities underlying these responses,7, 21 and then isolate bnAbs from these individuals 22, 23, 24, 25, 26, 27, 28. Independently, the standardization of the TZM‐bl neutralization assay and the definition of neutralization sensitivity tiers29, 30, 31 allowed much more rigorous serum analysis.…”