Probing the Interaction of Dengue Virus Envelope Protein with Heparin:  Assessment of Glycosaminoglycan-Derived Inhibitors

“…Surprisingly, with the exception of heparin A-6039, all tested heparin derivatives affected VLP binding when present at a concentration of 250 g/ml. This may be best explained by the higher degree of sulfation of heparin than of cell surface heparan sulfate (28), resulting in a stronger VLP binding to heparin-BSA-coated plates than to cell surface HSPGs.…”

Section: Resultsmentioning

confidence: 99%

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

Selinka

Giroglou

Nowak

et al. 2003

J Virol

117

115

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Cell surface heparan sulfate proteoglycans (HSPGs) serve as primary attachment receptors for human papillomaviruses (HPVs). To demonstrate that a biologically functional HPV-receptor interaction is restricted to a specific subset of HSPGs, we first explored the role of HSPG glucosaminoglycan side chain modifications. We demonstrate that HSPG O sulfation is essential for HPV binding and infection, whereas de-N-sulfated heparin interfered with VLP binding but not with HPV pseudoinfection. This points to differences in VLP-HSPG and pseudovirion-HSPG interactions. Interestingly, internalization kinetics of VLPs and pseudovirions, as measured by fluorescence-activated cell sorting analysis, also differ significantly with approximate half times of 3.5 and 7.5 h, respectively. These data suggest that differences in HSPG binding significantly influence postbinding events. We also present evidence that pseudovirions undergo a conformational change after cell attachment. A monoclonal antibody (H33.J3), which displays negligible effectiveness in preattachment neutralization assays, efficiently neutralizes cell-bound virions. However, no difference in H33.J3 binding to pseudovirions and VLPs was observed in enzyme-linked immunosorbent assay and virus capture assays. In contrast to antibody H33.B6, which displays equal efficiencies in pre-and postattachment neutralization assays, H33.J3 does not block VLP binding to heparin, demonstrating that it interferes with steps subsequent to virus binding. Our data strongly suggest that H33.J3 recognizes a conformation-dependent epitope in capsid protein L1, which undergoes a structural change after cell attachment.Human papillomaviruses (HPVs) are highly species-specific epitheliotropic DNA viruses. Of the more than 100 different genotypes, HPV type 16 (HPV16), HPV18, HPV31, HPV33, HPV35, HPV45, and HPV58 are most closely associated with cervical epithelial neoplasias and members of the group of HPV imposing a "high risk" for malignant progression to invasive genital carcinomas (30). The nonenveloped papillomavirus is composed of 360 copies of the major capsid protein L1, organized in 72 capsomeres, and probably 12 copies of the minor capsid protein L2 (1, 43). The encapsidated genome is an 8,000-bp circularized double-stranded DNA associated with cellular histones.Despite their considerable clinical significance, the initial steps leading to infection with these viruses, as well as the mechanisms involved in virus entry into host cells, have not yet been completely elucidated due to the limited growth properties of HPV in cell cultures and the ubiquitous expression of HPV-binding proteins. The use of virus-like particles (VLPs) (20,25,36,46,49) has helped in the study of the initial interaction of papillomavirus particles with cell surfaces. It was established that VLPs of many HPV types compete for binding to the same highly conserved proteinaceous attachment receptor. In contrast to L1, L2 protein was not essential for binding, since L1 VLPs bound as efficiently as L1L2 VLPs (32,3...

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“…56 A highly sulfated decasaccharide sequence binding Dengue envelop protein was effectively mimicked with a currently used polyanionic drug, suramin, suggesting a new antiviral application for this agent. 57,58 In the future, chemokines might also be examined to determine whether viruses are mimicking their heparin-binding domains.…”

Section: Pathogen Recognitionmentioning

confidence: 99%

Role of Glycosaminoglycans in Cellular Communication

2004

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Glycosaminoglycans are of critical importance in intercellular communication in organisms. This ubiquitous class of linear polyanions interacts with a wide variety of proteins, including growth factors and chemokines, which regulate important physiological processes. The presence of glycosaminoglycans on cell membranes and in the extracellular matrix also has resulted in their exploitation by infectious pathogens to gain access and entry into animal cells. This Account examines the structural and physical characteristics of these molecules responsible for their interaction with proteins important in cell-cell communication.

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Probing the Interaction of Dengue Virus Envelope Protein with Heparin: Assessment of Glycosaminoglycan-Derived Inhibitors

Cited by 111 publications

References 18 publications

Cellular Binding of Hepatitis C Virus Envelope Glycoprotein E2 Requires Cell Surface Heparan Sulfate

Cellular Binding of Hepatitis C Virus Envelope Glycoprotein E2 Requires Cell Surface Heparan Sulfate

Further Evidence that Papillomavirus Capsids Exist inTwo DistinctConformations

Role of Glycosaminoglycans in Cellular Communication

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