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Review
. 2019 May 31;431(12):2223-2247.
doi: 10.1016/j.jmb.2019.04.016. Epub 2019 Apr 24.

Protein and Glycan Mimicry in HIV Vaccine Design

Gemma E Seabright  1 , Katie J Doores  2 , Dennis R Burton  3 , Max Crispin  4
Affiliations
Review

Protein and Glycan Mimicry in HIV Vaccine Design

Gemma E Seabright et al. J Mol Biol. .

Abstract

Antigenic mimicry is a fundamental tenet of structure-based vaccinology. Vaccine strategies for the human immunodeficiency virus type 1 (HIV-1) focus on the mimicry of its envelope spike (Env) due to its exposed location on the viral membrane and role in mediating infection. However, the virus has evolved to minimize the immunogenicity of conserved epitopes on the envelope spike. This principle is starkly illustrated by the presence of an extensive array of host-derived glycans, which act to shield the underlying protein from antibody recognition. Despite these hurdles, a subset of HIV-infected individuals eventually develop broadly neutralizing antibodies that recognize these virally presented glycans. Effective HIV-1 immunogens are therefore likely to involve some degree of mimicry of both the protein and glycan components of Env. As such, considerable efforts have been made to characterize the structure of the envelope spike and its glycan shield. This review summarizes the recent progress made in this field, with an emphasis on our growing understanding of the factors shaping the glycan shield of Env derived from both virus and soluble immunogens. We argue that recombinant mimics of the envelope spike are currently capable of capturing many features of the native viral glycan shield. Finally, we explore strategies through which the immunogenicity of Env glycans may be enhanced in the development of future immunogens.

Keywords: antibodies; glycosylation; human immunodeficiency virus; structure; vaccinology.

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Structure of the HIV-1 virion and the envelope spike. (a) Graphic depicting the structure of the HIV-1 virion. Approximately 14 envelope spikes are displayed on the surface of the virion (mean for one HIV-1 isolate), embedded into the host cell-derived lipid membrane . (b) Model of a fully glycosylated envelope spike (glycans in cyan sticks) based on PDB: 5ACO . Glycans were added according to Behrens et al. . The envelope spike is a trimer of non-covalently associated gp120 (light gray) and gp41 (dark gray) heterodimers. The gp120 subunits contain the CD4 receptor and CCR5 or CXCR4 co-receptor binding sites. Upon binding, the trimer undergoes substantial conformational changes that enable the gp41 subunits to drive fusion of the viral and host cell membranes. The membrane proximal external region (MPER), transmembrane domain (TM) and cytoplasmic tail (CT) are not present on the structure and are shown for one protomer in cartoon along with the lipid membrane for orientation. (c) Left: Schematic representation of the primary structure of Env (top) and the soluble immunogen, BG505 SOSIP.664 (bottom). Variable regions (V1–5) are shown in colour, constant regions (C1–5) are shown in light gray, and gp41 is shown in dark gray. The envelope spike has approximately 25 potential N-glycosylation sites per gp120, and 4 per gp41 (cyan forks; mean across many isolates) . SOSIP.664 modifications are annotated in magenta, with optional purification tag coloured green. FP, fusion peptide; HR1/2, heptad repeat 1 and 2. Right: Model of a de-glycosylated envelope spike (as in panel b), with variable loops coloured accordingly.
Fig. 2
Fig. 2
Broadly neutralizing antibodies recognize protein‐glycan epitopes. Model of a fully glycosylated BG505 SOSIP.664 trimer depicting the N-glycans that have been implicated in binding a variety of bnAbs (inset key). Glycans not present on the BG505 strain have been omitted; for example, 35O22 also recognizes N-glycans at positions 230 and 241. Model based on PDB: 5ACO as in Fig. 1, numbering according to the HXB2 reference sequence. CD4bs, CD4 binding site.
Fig. 3
Fig. 3
Principles controlling Env glycosylation. Site-specific glycan analysis of recombinant BG505 SOSIP.664 , , , and virally derived BG505 Env , has revealed clusters of glycans displaying under-processed, oligomannose-type glycans (green). These are largely located on the outer domain of gp120 (forming the intrinsic mannose patch) and at the trimer apex and protomer interfaces (forming the trimer-associated mannose patch). Model according to Fig. 1. (a) The quaternary protein structure of native-like trimers imposes steric constraints on the host's glycosylation enzymes, resulting in an increase in the amount of oligomannose-type glycans at sites near the protomer interfaces (red/orange), compared to that of monomeric or non-native trimeric Env . (b) Irrespective of the mature Env peptide sequence, the presence of a signal peptide (SP) from a transmitted/founder (TF) viral isolate results in an increase in oligomannose-type glycosylation, while a chronic-stage signal peptide results in increased complex-type glycosylation. The signal peptide influences Env trafficking, folding and retention through the ER . (c) Modeling the ER α-mannosidase I (cyan, PDB: 5KIJ) on to its substrate glycan (green) reveals extensive clashes with neighboring glycans (red) sufficient to explain the formation of the intrinsic mannose patch . (d) It is hypothesized that membrane-bound Env constructs display elevated glycosylation processing as they exhibit a different topology relative to the membrane-bound enzymes compared to soluble constructs, which are released into the lumen of the ER , . Schematic of a membrane-bound glycan processing enzyme, based on the structure of a sialyltransferase (PDB: 6APL). (e) While the processing of many Env glycans is limited by protein-directed steric constraints, the fate of others is dependent on the glycosylation enzymes possessed by the host cell. The gp41 from BG505 SOSIP.664 expressed in Chinese hamster ovary (CHO) cells displays increased sialylation compared to the same protein expressed in human embryonic kidney (HEK) cells .
Fig. 4
Fig. 4
Overview of the mammalian N-glycosylation pathway. The envelope spike is extensively glycosylated by the host cell, which typically follows a highly ordered pathway. As the protein is translated, a Glc3Man9GlcNAc2 (Glc, glucose, Man, mannose, GlcNAc, N-acetylglucosamine) precursor is transferred en bloc to Asn residues within the N-glycan consensus sequence Asn-X-Thr/Ser (where X is any amino acid except Pro). As the protein is folded the three terminal glucose residues are removed to give rise to a glycoprotein displaying homogenous Man9GlcNAc2 structures. This is then further trimmed by endoplasmic reticulum (ER)- and Golgi apparatus-resident α-mannosidases to give rise to Man5GlcNAc2. Steric constraints within Env limit the actions of these early enzymes resulting in a population of under-processed oligomannose-type glycans. The addition of a β1-2-linked GlcNAc residue to Man5GlcNAc2 structures initiates cell-specific diversification to a variety of hybrid- and complex-type structures, through additional processing and/or trimming. α-man I and II, α-mannosidase I and II; GnT I, N-acetylglucosaminyltransferase I; Gal, galactose; Fuc, fucose; Neu5Ac, N-acetylneuraminic acid (sialic acid). Glycan structures are depicted in symbols according to the Consortium for Functional Glycomics nomenclature, with linkage information according to Oxford nomenclature, as shown in the key.
Fig. 5
Fig. 5
Glycan clustering and protein structure limit glycosylation processing on HIV-1. Quantitative glycan analysis of monomeric gp120, pseudotrimers, native-like trimers, and virally derived Env. For comparison, data for both gp120 and gp140 (gp120 + truncated gp41) from native-like trimers have been included, only data for virally derived gp120 were available , . Each construct is based on the BG505 sequence containing the T332N mutation. Glycans were enzymatically released, fluorescently labeled, and analyzed by hydrophilic interaction liquid chromatography–ultraperformance liquid chromatography. Oligomannose-type glycans were quantified by their susceptibility to digestion with Endoglycosidase H. The chromatograms reveal a population of oligomannose-type glycans (green) intrinsic to all Env constructs, termed the intrinsic mannose patch (IMP). Only native-like trimers and virally derived Envs display the additional trimer-associated mannose patch (TAMP) signature, attributed to additional steric protection from processing.
Fig. 6
Fig. 6
Antigenic mimicry in autoimmune disease and HIV-1 vaccine design. (a) Antigenic mimicry of lipooligosaccharides (LOS) from C. jejuni causes Guillain–Barré syndrome, an autoimmune response against the GM1 ganglioside in the peripheral nervous system (PNS). (b) LOS from Rhizobium radiobacter Rv3 and Saccharomyces cerevisiae deficient in the Mnn1 gene display glycan structures terminating in α1-2-linked mannose residues, mimicking the 2G12 epitope on HIV-1. GalNAc, N-acetylgalactosamine; Glc, gluscose; GlcN, glucosamine; KDO, 2-keto-3-deoxy-D-manno-octulosonic acid. Figure adapted from Scanlan et al. .
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