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Review
. 2020 Sep;15(5):267-274.
doi: 10.1097/COH.0000000000000639.

Hitting the sweet spot: exploiting HIV-1 glycan shield for induction of broadly neutralizing antibodies

Kshitij Wagh  1 , Beatrice H Hahn  2 , Bette Korber  1   3
Affiliations
Review

Hitting the sweet spot: exploiting HIV-1 glycan shield for induction of broadly neutralizing antibodies

Kshitij Wagh et al. Curr Opin HIV AIDS. 2020 Sep.

Abstract

Purpose of review: The surface of the HIV-1 Env glycoprotein, the target of neutralizing antibodies, is extensively covered by N-linked glycans that create a glycan shield. Broadly neutralizing antibodies (bNAbs), the primary targets of HIV-1 vaccine design, have to negotiate this glycan shield. Here, we review the barriers and opportunities that the HIV-1 glycan shield presents for vaccine induction of bNAbs.

Recent findings: Glycan shields can impact the nature of the antibody response and influence the development of neutralization breadth in HIV-1 infections. The architecture of the glycan shield arising from glycan interactions and dynamics have been modeled, and its fine structure, that is, the site-wise glycan heterogeneity, has been determined for some isolates. Although the extent of glycan shielding is conserved, the precise number, location and processing of glycans, however, is strain-dependent. New insights continue to reveal how such differences can impact bNAb activity and development. Novel approaches have exploited the glycan shield for designing immunogens that bind the germline precursors of bNAbs, a critical roadblock for vaccine-induction of bNAbs.

Summary: The HIV-1 glycan shield can significantly impact the induction and maturation of bNAbs, and a better understanding of how to manipulate it will improve immunogen design.

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Conflict of interest statement

Conflicts of interests

None.

Figures

Figure 1.
Figure 1.
Conservation of glycans and the glycan shield in M-group Envs. (A) Distribution of unique (i.e. per protomer) glycans in an alignment of ~4,800 M-group Envs (2018 Filtered Web alignment from the Los Alamos HIV Database, www.hiv.lanl.gov). Hypervariable loop glycans are excluded. (B) Distribution of glycan frequency in M-group Envs. Hypervariable loop glycans and glycans with <10% frequency are excluded. (C) Structural mapping of glycan sites in (B). PDB: 5FYJ [1]. (D) Conservation of glycan shielding in M-group using the calculations from Wagh et al. [*]. Original.
Figure 2
Figure 2
Pros and cons of immunogens with varying glycan shields. Left: An Env with a glycan hole at N276 is shown, similar to CD4bs germline targeting immunogens. Middle: An Env with complete glycan shield is shown. Right: An Env with all conserved glycans, but grown in GnTI knockout cell-lines is shown. The pros and cons for each immunogen type are listed based on discussion in the text. Glycans were modeled on BG505 trimer structure PDB: 5FYL [1] using GlyProt (www.glycosciences.de) with default oligomannose or complex glycans, or Man5 for GnTI-. Missing glycans in BG505 at sites 130, 241 and 289 were artificially introduced. For left and middle panels, information from Cao et al. [**] was used on whether a site is predominantly oligomannose or complex. For the right panel, all complex glycans in the middle panel were replaced by Man5 to approximate GnTI- activity. Original
See this image and copyright information in PMC

References

    1. Stewart-Jones GBE, Soto C, Lemmin T, Chuang G-Y, Druz A, Kong R, et al. Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G. Cell 2016;165:813–26. 10.1016/j.cell.2016.04.010. - DOI - PMC - PubMed
    1. Korber B, Hraber P, Wagh K, Hahn BH. Polyvalent vaccine approaches to combat HIV-1 diversity. Immunological Reviews 2017;275:230–44. 10.1111/imr.12516. - DOI - PMC - PubMed

    1. Bricault CA, Yusim K, Seaman MS, Yoon H, Theiler J, Giorgi EE, et al. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host & Microbe 2019;25:59–72.e8. 10.1016/j.chom.2018.12.001.

      * In this study, we identified a comprehensive set of sequence (amino acid, glycans and hypervariable region characteristics) signatures associated with activity of multiple bNAbs from each major bNAb-class.

    1. Stephenson KE, Wagh K, Korber B, Barouch DH. Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention. Annual Review of Immunology 2020;38:673–703. 10.1146/annurev-immunol-080219-023629. - DOI - PMC - PubMed

    1. Wagh K, Kreider EF, Li Y, Barbian HJ, Learn GH, Giorgi E, et al. Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth. Cell Reports 2018;25:893–908.e7. 10.1016/j.celrep.2018.09.087.

      * In this study, we developed an approximate but accurate strategy to map glycan shields for a given Env sequence, and used this to explore the impact of glycan shield evolution on bNAb development.

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