Glycan Positioning Impacts HIV-1 Env Glycan-Shield Density, Function, and Recognition by Antibodies

Wei, Qing; Hargett, Audra A.; Knoppová, Barbora; Duverger, Alexandra; Rawi, Reda; Shen, Chen‐Hsiang; Farney, S. Katie; Hall, Stacy; Brown, Raymond Albert Joseph; Keele, Brandon F.; Heath, Sonya L.; Saag, Michael S.; Kutsch, Olaf; Chuang, Gwo-Yu; Kwong, Peter D.; Moldoveanu, Zina; Raška, Milan; Renfrow, Matthew B.; Novák, Jan

doi:10.1016/j.isci.2020.101711

Cited by 5 publications

(3 citation statements)

References 59 publications

(124 reference statements)

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“…Variable loop lengths and the total serine/threonine (S/T) counts were determined within each individual variable region (V1 to V5). The variable region coordinates were determined using the following HXB2 amino acid (AA) positions (GenBank accession number K03455 ): V1, AA 127 to 156; V2, AA 160 to 195; V3, AA 300 to 328; V4, AA 393 to 414; and V5, AA 460 to 470 ( 81 ). The number of potential N-linked glycosylation sites (PNGSs) were ascertained using the N-Glycosite tool from the Los Alamos HIV database website ( http://www.hiv.lanl.gov/content/sequence/GLYCOSITE/glycosite.html ; accessed 10 April 2020).…”

Section: Methodsmentioning

confidence: 99%

Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection

Mandizvo

Gumede

Ndlovu

et al. 2022

J Virol

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Section: Methodsmentioning

confidence: 99%

Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection

Mandizvo

Gumede

Ndlovu

et al. 2022

J Virol

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“…IgG sialylation has been linked to anti-inflammatory activity [ 19 ]. The loss of some HIV-1 gp120 glycans leads to an increase in protein degradation and a decrease in binding to the host cell receptor [ 20 , 21 , 22 ]. In Hepatitis C virus envelope 2 protein, the loss of either N2 or N4 glycan results in total loss of HCV infectivity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Glycosylation States on Intact Proteins Determined by NMR Spectroscopy

Hargett

Marcella

et al. 2021

Molecules

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Protein glycosylation is important in many organisms for proper protein folding, signaling, cell adhesion, protein-protein interactions, and immune responses. Thus, effectively determining the extent of glycosylation in glycoprotein therapeutics is crucial. Up to now, characterizing protein glycosylation has been carried out mostly by liquid chromatography mass spectrometry (LC-MS), which requires careful sample processing, e.g., glycan removal or protein digestion and glycopeptide enrichment. Herein, we introduce an NMR-based method to better characterize intact glycoproteins in natural abundance. This non-destructive method relies on exploiting differences in nuclear relaxation to suppress the NMR signals of the protein while maintaining glycan signals. Using RNase B Man5 and RNase B Man9, we establish reference spectra that can be used to determine the different glycoforms present in heterogeneously glycosylated commercial RNase B.

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“…This approach was able to detect subtle changes in PNGS occupancy, glycan compositions and glycan dynamics that can impact the structure of the glycan shield and epitope accessibility [ 99 ]. Further in silico studies using molecular dynamics simulations attempted to predict glycan movement for HIV‐1 and SARS‐CoV‐2 [ 100 , 101 ]. A better understanding and visualization of the dynamics of the glycan shield helps to understand how bNAbs cope with the glycan shield and how we need to consider this in vaccine design efforts.…”

Section: Discussionmentioning

confidence: 99%

Structure‐guided envelope trimer design in HIV‐1 vaccine development: a narrative review

Derking

Sanders

2021

J Int AIDS Soc.

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IntroductionThe development of a human immunodeficiency virus 1 (HIV‐1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native‐like HIV‐1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure‐guided HIV‐1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV‐1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve “on‐target” antibody responses versus “off‐target” responses.MethodsThe authors conducted a narrative review of recently published articles that made a major contribution to HIV‐1 structural biology and vaccine design efforts between the years 2000 and 2021.DiscussionThe field of structural biology is evolving at an unprecedented pace, where cryo‐electron microscopy (cryo‐EM) and X‐ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy‐based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off‐target responses, while improving immunogens to drive the more desirable on‐target responses.ConclusionsResolving high‐resolution structures of the HIV‐1 Env trimer was instrumental in understanding and improving recombinant HIV‐1 Env trimers that mimic the structure of viral HIV‐1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV‐1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.

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Glycan Positioning Impacts HIV-1 Env Glycan-Shield Density, Function, and Recognition by Antibodies

Cited by 5 publications

References 59 publications

Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection

Subtle Longitudinal Alterations in Env Sequence Potentiate Differences in Sensitivity to Broadly Neutralizing Antibodies following Acute HIV-1 Subtype C Infection

Glycosylation States on Intact Proteins Determined by NMR Spectroscopy

Structure‐guided envelope trimer design in HIV‐1 vaccine development: a narrative review

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