Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor

Abstract

Summary VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged within a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. Structures revealed a VRC01-like angle of approach, but less favorable interactions between DRVIA7 light chain CDR1 and N-terminus with N276 and V5 glycans on gp120. While the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light chain CDR3 signature and VRC01-like neutralizing heavy chain precursors that rapidly matured within two years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.

Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires

“…Structural studies suggest that overcoming this roadblock will require remodeling of the CDR L1 region. In one case of a VRC01-class antibody (DRVIA7) that failed to attain broad neutralization (Kong et al, 2016), N276 appears to clash with CDR L1; the same problem may have hindered further maturation of VRC01 type of antibodies in our immunization experiments. In mature VRC01-class antibodies, extensive remodeling of CDR L1, including small deletions, established favorable contacts with N276.…”

“…None of the isolated antibodies from our current immunizations have attained broad neutralizing status, and additional boosts with appropriate immunogens will be required to further mature the VRC01 intermediates. A major hurdle is N276 glycosylation, which also posed a roadblock to the maturation of VRC01 class antibodies in two HIV-1 infected individuals (Kong et al, 2016; Wu et al, 2012; Wu et al, 2015). Structural studies suggest that overcoming this roadblock will require remodeling of the CDR L1 region.…”

Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller

“…This response is associated with selection for resistant viral variants that, in some cases, elicit bNAbs (5, 12, 31, 49–51). However, the individuals studied in detail differ from EB354 in that the development of bNAbs is associated with rapid selection of autologous plasma viruses, which are resistant to coexisting bNAbs (6–9, 52, 53). Donor EB354 is significant because sensitive and resistant viral strains coexist with bNAbs, and the resistant strains fail to produce high levels of viremia because the viral strains are either in some way partially effective or kept in check by CD8+ T cells.…”

Identification and specificity of broadly neutralizing antibodies against HIV

“…Within the genetically restricted subclass, the potent VRC01‐like antibodies use only the VH1‐2 V gene and also share an unusual short light chain motif, unlike VH1‐46 V gene bnAbs 57, 76, 77. Recently, it has been shown that while VRC01‐like heavy chains can mature relatively rapidly, generation of light chains that are able to accommodate glycans obstructing access to the epitope takes longer 78. In contrast, the CD4‐binding site bnAbs that bind via their CDRH3 are drawn from a wide variety of V genes, have no conserved binding motif, but approach the trimer from similar angles 76.…”