Glycoengineering HIV-1 Env creates ‘supercharged’ and ‘hybrid’ glycans to increase neutralizing antibody potency, breadth and saturation

Crooks, Ema T.; Grimley, Samantha L.; Cully, Michelle D.; Osawa, Keiko; Dekkers, Gillian; Saunders, Kevin O.; Rämisch, Sebastian; Menis, Sergey; Schief, William R.; Doria‐Rose, Nicole A.; Haynes, Barton F.; Murrell, Ben; Cale, Evan M.; Pegu, Amarendra; Mascola, John R.; Vidarsson, Gestur; Binley, James Μ.

doi:10.1371/journal.ppat.1007024

PLoS Pathog

2018

DOI: 10.1371/journal.ppat.1007024

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Glycoengineering HIV-1 Env creates ‘supercharged’ and ‘hybrid’ glycans to increase neutralizing antibody potency, breadth and saturation

Ema T. Crooks

¹

,

Samantha L. Grimley

²

,

Michelle D. Cully

³

et al.

Abstract: The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env glycan maturation regulates HIV sensitivity to bnAbs, we modified HIV-1 pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the maturation of α-2,6 sialic acid (SA) glycan termini increased PV sensitivity to two bnAbs th… Show more

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Cited by 31 publications

(92 citation statements)

References 104 publications

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“…As expected, NFL eliminated gp120 and gp41 bands (missing red and green dots, respectively in lanes 2–10). Consistent with previous studies [ 30 , 34 , 39 , 43 – 46 , 63 , 64 ], we detected two forms of gp160: a “mature” gp160 (gp160m, magenta dots) bearing complex glycans and an “immature” gp160 (gp160i, yellow dots) bearing high mannose glycans. In NFL mutants, the gp120 band of the SOS parent ( Fig 2A , lane 1 red dot) was replaced by gp160m ( Fig 2A , lane 2, magenta dot), indicating that, in the absence of a NFL linker, gp160m is partially processed into gp120 and gp41.…”

Section: Resultssupporting

confidence: 92%

“…Overall, these findings suggest a scenario in which glycans progressively mature as gp160 disulfides isomerize and exchange until they reach the canonical native conformation, by which point glycans are most differentiated. This is consistent with previous observations that live HIV-1 is heavily sialylated [ 46 , 72 , 76 , 77 ]. A less mature glycan profile may therefore signify aborted attempts to reach the final native conformation and may be a marker of misfolding.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Impact of stabilizing mutations on the antigenic profile and glycosylation of membrane-expressed HIV-1 envelope glycoprotein

Tong

¹

,

D’Addabbo

²

,

Xu

³

et al. 2023

Self Cite

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Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…As expected, NFL eliminated gp120 and gp41 bands (missing red and green dots, respectively in lanes 2–10). Consistent with previous studies [ 30 , 34 , 39 , 43 – 46 , 63 , 64 ], we detected two forms of gp160: a “mature” gp160 (gp160m, magenta dots) bearing complex glycans and an “immature” gp160 (gp160i, yellow dots) bearing high mannose glycans. In NFL mutants, the gp120 band of the SOS parent ( Fig 2A , lane 1 red dot) was replaced by gp160m ( Fig 2A , lane 2, magenta dot), indicating that, in the absence of a NFL linker, gp160m is partially processed into gp120 and gp41.…”

Section: Resultssupporting

confidence: 92%

“…Overall, these findings suggest a scenario in which glycans progressively mature as gp160 disulfides isomerize and exchange until they reach the canonical native conformation, by which point glycans are most differentiated. This is consistent with previous observations that live HIV-1 is heavily sialylated [ 46 , 72 , 76 , 77 ]. A less mature glycan profile may therefore signify aborted attempts to reach the final native conformation and may be a marker of misfolding.…”

Section: Discussionsupporting

confidence: 93%

Impact of stabilizing mutations on the antigenic profile and glycosylation of membrane-expressed HIV-1 envelope glycoprotein

Tong

¹

,

D’Addabbo

²

,

Xu

³

et al. 2023

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…The 7- and 5- mannose models provided better Ab accessibility than the 9-mannose model (median depth of 11.1 Å, 12.2 Å and 13.6 Å for 5-, 7 and 9-mannose Env models, respectively), indicating that engineering the glycan shield to have only 5 or 7 mannose residues at each glycan site may improve Ab accessibility. This is consistent with the finding that restricting the glycan site to be 5 mannose greatly increased its susceptibility to an array of bnAbs[26].…”

Section: Resultssupporting

confidence: 91%

The breadth of HIV-1 neutralizing antibodies depends on the conservation of key sites in their epitopes

Bai

¹

,

Li

²

,

Michael

³

et al. 2019

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…EPVs produced in GnT1 - cells were more sensitive to HIV-1 sera than their 293T-grown counterpart, especially TM1 and TM4, but still within the tier 2 spectrum. These results agree with the tier 2 phenotype of other EPV produced in GnT1 - cells [ 58 ]. We note that the 293S GnT1 - viruses often exhibited lower infectivity than their 293T-grown counterparts.…”

Section: Resultssupporting

confidence: 90%

“…Several mature CD4bs bnAbs were substantially more potent against Man 5 -enriched Envs than wild type Envs, while most bnAbs to epitopes outside the CD4bs were unaffected. One exception is the negative impact Man 5 -enrichment had on PGT151, which was observed before [ 58 ] and agrees with previous reports that PGT151 requires one or more complex-type glycans [ 60 , 61 ]. In another study, Man 5 -enrichment had only modest effects on mature CD4bs bnAbs and had more dramatic effects on V2 apex and gp120/gp41 interface bnAbs than we observed [ 58 ].…”

Section: Discussionsupporting

confidence: 91%

HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies

LaBranche

¹

,

McGuire

²

,

Gray

³

et al. 2018

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

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