HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design

Abstract

SummaryEliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.

Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail

“…As an example, Figure 6B shows the shortest paths to all glycans from the glycan at site N332. The site N332 is central in the glycan interaction network, and is known to have both direct and subtle long-range influences over a number of bNAb sites[7, 69]. Our calculation shows the most probable pathway over which each glycan feels the influence of the glycan at site N332.…”

“…While each glycan exerts effects in its immediate vicinity, due to the inter-glycan interactions, their influence can percolate over long distances across the surface of protein. Long-range glycan interactions can occur, as with perturbation of a glycan at one site can affect the processing and antibody interactions of another glycan at a distant site[7, 18, 23, 69]. Understanding long-range interactions between glycans is important for characterizing global properties of the glycan shield.…”

“…In this study, we have found that this area can vary, depending on the glycan type, charge, neighbors, etc. Amino acid signature analyses suggest that even minor perturbations such as single site mutations could potentially change the shielding effect over certain epitope regions[69]. Therefore, we have derived a measure to quantify the shielding effect based on the encounter factor of glycan over the antigenic protein surface.…”

Harnessing Avidity: Quantifying Entropic and Energetic Effects of Linker Length and Rigidity Required for Multivalent Binding of Antibodies to HIV-1 Spikes

“…To further enhance potency, more than three Fabs could be joined together into a multiFab. By joining multiple types of Fabs that bind to different epitopes (e.g., the broadly neutralizing CD4binding 3BNC117 with a V1V2-binding PG16), multiFabs may enhance the potency of neutralization as well as help combat HIV-1 heterogeneity as has been seen in combination influenza antibodies (51) and HIV-1 mosaic vaccines (52).…”

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir

“…High-resolution imaging approaches have revealed that bNAb and glycan interactions are common across all bNAb classes, and previous analyses to map antibody binding and antibody neutralization activity depended not only on sequence, but also on glycan occupancy (18,19). Computational approaches for prediction of neutralization sensitivity based on Env sequences have been reported previously (20)(21)(22). Information of glycans and glycan occupancy, however, have not been included in these models, therefore excluding a critical component.…”