Identification of Common Features in Prototype Broadly Neutralizing Antibodies to HIV Envelope V2 Apex to Facilitate Vaccine Design

Abstract

Summary Broadly neutralizing antibodies (bnAbs) directed to the V2 apex of the HIV envelope (Env) trimer isolated from individual HIV-infected donors potently neutralize diverse HIV strains, but strategies for designing immunogens to elicit bnAbs have not been identified. Here, we compared four prototypes (PG9, CH01, PGT145 and CAP256.VRC26.09) of V2 apex bnAbs and showed that all recognized a core epitope of basic V2 residues and the glycan-N160. Two prototype bnAbs were derived from VH-germlines that were 99% identical and used a common germline D-gene encoded YYD-motif to interact with the V2-epitope. We identified viruses that were neutralized by iGL from three prototype bnAbs and soluble Env derived from one of the isolates was shown to form a well-ordered Env trimer that mimics that on the surface of virions and could serve to initiate a V2-apex bnAb response. These studies illustrate a strategy to transition from panels of bnAbs to vaccine candidates.

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.…”

“…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. Furthermore, while N160 is absolutely required for only three out of four prototypes, CAP256.09 is only partially dependent on a glycan at this position 51, 68. There are also differences in the particular glycans preferred by each prototype, with variations even between PG9 and PG16, which prefer glycans with α‐2‐3 and α‐2‐6 linked sialic acid terminal sugars, respectively 68, 69.…”

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

“…Man 5 GlcNac 2 (52). V1V2 bnAb interactions with various glycans and direct strand-strand contact between the extended CDR H3 and the C strand of the V1V2 domain are common traits among individual V1V2 bnAbs (51, 52, 55, 56). For immunogen design, despite V1V2 glycan bnAb preference for binding to a quaternary epitope, PG9, PG16 and CH01 bnAbs, as well as the CH01 lineage unmutated common ancestor (UCA), can also bind a minor subset of monomeric gp120 Envs (15, 57) and minimal Env forms (58).…”

“…While such immunogens are designed for the UCA and intermediate antibodies of one particular bnAb lineage, they hold promise for inducing bnAb lineages in multiple individuals because of the remarkable conserved usage of V H and V L genes of bnAbs and the restricted nature of antibody motifs for many bnAb types, particularly for the gp41 membrane proximal region (89), the CD4 binding site (42) and the V1V2-glycan site (15, 41, 55, 56). To mimic the progression of maturation of bnAb lineages, each Env should engage a bnAb precursor with affinity sufficient to trigger the B cell but with low binding affinity to allow for affinity maturation to the next stage of bnAb development.…”

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

“…In addition to providing insight into natural antibody repertoires, we have explored synthetic antibody libraries skewed to include unusual features observed in broadly neutralizing antibodies that target HIV‐1, such as long protruding loops and tyrosine sulfation 11, 102, 118, 119. We observed antibodies from libraries enriched in long anionic loops, similar to those observed in antibodies PG9, CH01, and CAP256‐VRC26,6, 11, 28, 37, 102 to have poor solubility.…”