Analysis of a Clonal Lineage of HIV-1 Envelope V2/V3 Conformational Epitope-Specific Broadly Neutralizing Antibodies and Their Inferred Unmutated Common Ancestors

Abstract

V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies.

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

“…The difficulty in eliciting bnAbs has been attributed to the enormous antigenic diversity of the envelope glycoprotein and to the dense N-linked glycan coat that covers Env (the ‘glycan shield’). BnAbs isolated from chronic infection have a number of unusual features that have been selected to cope with the glycan shield including much longer than average HCDR3 loops 10–12 . HCDR3s in most vertebrates have restricted lengths that predominantly encode loops of 12–16 amino acids upon VDJ recombination 9,13–15 .…”

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

“…The V1V2-glycan bnAb class was the first of the new generation of bnAbs discovered (14, 15) (McCoy and Burton this volume). V1V2-glycan bnAbs, such as the PG9, CH01, PGT145 and CAP256-VRC26 lineages, are characterized by anionic, often tyrosine-sulfated, long and protruding CDR H3s that penetrate HIV envelope glycans and recognize a discontinuous epitope at the apex of the HIV-1 spike (14, 15,19,22,25,51–54).…”

“…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). Crystal structures of the V1V2 glycan Env region in complex with V2 antibodies demonstrated that the V1V2 epitope can assume at least three conformations (52, 57): a β-strand, an α-helix and a 3 10 helix.…”

“…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.…”

“…We have now reconstructed bnAb lineages from a number of HIV-1 infected individuals that made either gp41 membrane proximal lineage bnAbs (89, 98) (Williams L., Haynes B.F. et al unpublished), CD4bs bnAbs (16–18), V1V2-glycan bnAbs (15) or V3-glycan bnAbs (Bonsignori M. et al, submitted). Here we discuss the use of antibody and virus co-evolution mapping data to design a first generation of immunogens for induction of two types of CD4bs bnAb B cell lineages, CDR H3-binder and V H 1-46 CD4 mimicking CD4bs bnAbs, and for V3-glycan bnAbs (see also Korber, Hraber, Wagh and Hahn, this volume).…”