Differential processing of HIV envelope glycans on the virus and soluble recombinant trimer

Cao, Liwei; Pauthner, Matthias; Andrabi, Raiees; Rantalainen, Kimmo; Berndsen, Zachary T.; Diedrich, Jolene K.; Menis, Sergey; Sok, Devin; Bastidas, Raiza; Park, Sung Kyu Robin; Delahunty, Claire; He, Lin; Guenaga, Javier; Wyatt, Richard T.; Schief, William R.; Ward, Andrew B.; Yates, John R.; Burton, Dennis R.; Paulson, James C.

doi:10.1038/s41467-018-06121-4

Cited by 133 publications

(175 citation statements)

References 67 publications

(121 reference statements)

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“…This observation is in line with the earlier overall glycan profile of pseudoviral gp160 of JR-CSF and BG505 SOSIP.664 trimers [43][44][45]. In addition, these observations are consistent with recent comparison of full-length virallyderived Env with corresponding soluble SOSIP [26,27]. In these studies, glycosylation sites displaying a mixed population of oligomannose and complex glycans in the SOSIP format were more uniformly of the complex type.…”

Section: Composition Of Individual Glycans On Full-length and Sosip Tsupporting

confidence: 91%

“…The results show that the antigenic profile and glycan composition of full-length and SOSIP trimers was similar, but also revealed subtle and interesting differences. In a similar manner to previous observations comparing virally derived N-glycans and corresponding SOSIP trimers [26,27], there was a noticeable decrease in the number and processing of complex-type glycans on the SOSIP trimer. This most likely can be attributed to its enhanced stability and reduced conformational breathing due to the presence of the SOSIP mutations, as well as the lack of the membrane tether.…”

Section: Introductionsupporting

confidence: 88%

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Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

Peña

Rantalainen

Cottrell

et al. 2018

Preprint

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The HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant nativelike soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length native Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV + individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of fulllength and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated fulllength and soluble SOSIP HIV-1 Env trimers as immunogens.

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Section: Composition Of Individual Glycans On Full-length and Sosip Tsupporting

confidence: 91%

Section: Introductionsupporting

confidence: 88%

Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

Peña

Rantalainen

Cottrell

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, one study reported on the elicitation of glycan-dependent antibodies resembling precursors of human bnAbs to the oligomannose patch in nontransgenic animals using a 'designer' SOSIP-based trimer 56 . Despite potential advantages of SOSIP-based immunogens, one probable disadvantage is glycosylation heterogeneity, which has been experimentally shown to be greater at several Nglycosylation sites compared to native Env 40 . Synthetic oligomannosides offer an attractive alternative in this regard, enabling production of structurally defined immunogens.…”

Section: Discussionmentioning

confidence: 99%

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

Bruxelle

Kirilenko

Qureshi

et al. 2020

Preprint

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ABSTRACTOligomannose-type glycans on HIV-1 gp120 form a patch that is targeted by several broadly neutralizing antibodies (bnAbs) and that therefore is of interest to vaccine design. However, attempts to elicit similar oligomannose-specific bnAbs by immunizing with oligomannosidic glycoconjugates have only been modestly successful so far. A common assumption is that eliciting oligomannose-specific bnAbs is hindered by B cell tolerance, resulting from the presented oligomannosides being sensed as self molecules. Here, we present data, along with existing scientific evidence, supporting an additional, or perhaps alternate, explanation: serum mannosidase trimming of the presented oligomannosides in vivo. Mannosidase trimming lessens the likelihood of eliciting antibodies with capacity to bind full-sized oligomannose, which typifies the binding mode of existing bnAbs to the oligomannose patch. The rapidity of the observed trimming suggests the need for immunization strategies and/or synthetic glycosides that readily avoid or resist mannosidase trimming upon immunization and can overcome possible tolerance restrictions.

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“…Whilst the oligomannose-type glycan content is well above that observed on typical host glycoproteins, it is significantly lower than is found on other viral glycoproteins. For example, one of the most densely glycosylated viral spike proteins is HIV-1 Env, which contains ~60% oligomannose-type glycans 20,37 . This suggests that SARS-CoV-2 S protein is less densely glycosylated and that the glycans form much less of a shield compared with other viral glycoproteins including HIV Env and LASV GPC, which may be beneficial for the elicitation of potent neutralizing antibodies.…”

Section: Fully Glycosylated Model Of the Sars-cov-2 Spikementioning

confidence: 99%

Site-specific analysis of the SARS-CoV-2 glycan shield

Watanabe

Allen

Wrapp

et al. 2020

Preprint

164

181

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The emergence of the betacoronavirus, SARS-CoV-2 that causes COVID-19, represents a significant threat to global human health. Vaccine development is focused on the principal target of the humoral immune response, the spike (S) glycoprotein, that mediates cell entry and membrane fusion. SARS-CoV-2 S gene encodes 22 N-linked glycan sequons per protomer, which likely play a role in immune evasion and occluding immunogenic protein epitopes. Here, using a site-specific mass spectrometric approach, we reveal the glycan structures on a recombinant SARS-CoV-2 S immunogen. This analysis enables mapping of the glycanprocessing states across the trimeric viral spike. We show how SARS-CoV-2 S glycans differ from typical host glycan processing, which may have implications in viral pathobiology and vaccine design.

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Differential processing of HIV envelope glycans on the virus and soluble recombinant trimer

Cited by 133 publications

References 67 publications

Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics

Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

Site-specific analysis of the SARS-CoV-2 glycan shield

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