Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail.

Srirupa Chakraborty,Bette T Korber,Zachary T Berndsen,Nicolas W Hengartner,S Gnanakaran,Andrew B Ward

doi:10.1016/j.isci.2020.101836

Srirupa Chakraborty, Bette T Korber + Show 4 more

Open Access

https://doi.org/10.1016/j.isci.2020.101836

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Abstract

SummaryDense surface glycosylation on the HIV-1 envelope (Env) protein acts as a shield from the adaptive immune system. However, the molecular complexity and flexibility of glycans make experimental studies a challenge. Here we have integrated high-throughput atomistic modeling of fully glycosylated HIV-1 Env with graph theory to capture immunologically important features of the shield topology. This is the first complete all-atom model of HIV-1 Env SOSIP glycan shield that includes both oligomannose and complex glycans, providing physiologically relevant insights of the glycan shield. This integrated approach including quantitative comparison with cryo-electron microscopy data provides hitherto unexplored details of the native shield architecture and its difference from the high-mannose glycoform. We have also derived a measure to quantify the shielding effect over the antigenic protein surface that defines regions of relative vulnerability and resilience of the shield and can be harnessed for rational immunogen design.

Highlights

Protein glycosylation is an essential aspect of post-translational modification, with 50%–70% of human proteins been estimated to be glycosylated to some degree (An et al, 2009)
SUMMARY Dense surface glycosylation on the HIV-1 envelope (Env) protein acts as a shield from the adaptive immune system
Selection of Site-Specific Glycans for Native Glycosylation of HIV-1 Env The soluble, recombinant BG505 SOSIP.664 trimer has been well characterized as a native-like, Env-mimetic model and serves as the prototypical immunogen in several vaccine development programs (Sanders et al, 2013, 2015)

Summary

Introduction

Protein glycosylation is an essential aspect of post-translational modification, with 50%–70% of human proteins been estimated to be glycosylated to some degree (An et al, 2009). Envelope proteins from several high-risk viral pathogens that hijack the host protein production and glycosylation machineries, such as HIV (lentivirus) (Burton and Mascola, 2015), Coronavirus (Walls et al, 2016; Vankadari and Wilce, 2020), Lassa (arenavirus) (Sommerstein et al, 2015), Hepatitis C (flavivirus) (Zhang et al, 2017), Epstein Barr (herpesvirus) (Szakonyi et al, 2006), Ebola (filovirus) (Lennemann et al, 2014; Ilinykh et al, 2018), and Influenza (Wang et al, 2009) are heavily glycosylated These surface-expressed viral proteins are important immunological targets for neutralizing antibodies that can block viral infection of cells and form the primary focus of vaccine studies (Amanat et al, 2018; Saphire et al, 2018). A deeper molecular-level understanding of the glycan shields in these pathogenic viruses may help inform vaccine design strategies that can overcome this protective barrier

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