Protein and Glycan Mimicry in HIV Vaccine Design. Issue 12 (31st May 2019)

• Record Type: Journal Article
• Authors: Seabright, Gemma E.; Doores, Katie J.; Burton, Dennis R.; Crispin, Max
• Is Part Of: Journal of molecular biology. Volume 431:Issue 12(2019)
• Page Start: 2223
• Page End: 2247
• Publication Date: 2019-05-31
• Subjects: HIV-1 human immunodeficiency virus type 1 -- Env envelope spike -- AIDS acquired immune deficiency syndrome -- bnAb(s) broadly neutralizing antibody(ies) -- nAb(s) neutralizing antibody(ies) -- gl-bnAb(s) germline-bnAb(s) -- CD4bs CD4 binding site -- CCR5 C-C chemokine receptor type 5 -- CXCR4 C-X-C chemokine receptor type 4 -- TF transmitted/founder -- EM electron microscopy -- PNGS potential N-glycosylation sites -- BCR B cell receptor -- IMP intrinsic mannose patch -- TAMP trimer-associated mannose patch -- HCDR3 third heavy-chain complementarity-determining regions -- CDR complementarity-determining regions -- LOS lipooligosaccharides -- SP signal peptide -- MPER membrane proximal external region -- TM transmembrane region -- CT cytoplasmic tail -- HR1/2 heptad repeat 1 or 2 -- NFL native flexibly linked -- SC single-chain -- UFO uncleaved prefusion-optimized -- PBMC peripheral blood mononuclear cell -- PNS peripheral nervous system -- CHO Chinese hamster ovary -- HEK human embryonic kidney -- cGMP current good manufacturing practices -- Glc glucose -- Man mannose -- GlcNAc N-acetylglucosamine -- Gal galactose -- Fuc fucose -- Neu5Ac N-acetylneuraminic acid (sialic acid) -- GlcN glucosamine -- KDO 2-keto-3-deoxy-D-manno-octulosonic acid -- ER endoplasmic reticulum -- α-man I and II α-mannosidase I and II -- GnT I N-acetylglucosaminyltransferase I; human immunodeficiency virus -- vaccinology -- antibodies -- glycosylation -- structure; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2019.04.016
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical Abstract: Unlabelled Image Highlights: A focus of HIV-1 vaccine design is the development of soluble, recombinant envelope spike mimics. The envelope spike glycan shield acts to protect the underlying protein from immune recognition but can be targeted by broadly neutralizing antibodies. An understanding of the factors shaping viral and immunogen glycosylation will help guide the design of immunogens. Protein structural mimicry of HIV immunogens helps drive mimicry of the dense glycan coat. Strategies that increase the immunogenicity of glycan-dependent epitopes are likely to be required.