The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus entry into host cells.

Dipanwita Mitra,Mohammad H Hasan,Joshua S Sharp,Fuming Zhang,Robert J Linhardt,Quntao Liang,John T Bates,Ritesh Tandon,Hong Qiu,Rinkuben C Parmar,Vaibhav Tiwari,Lauren A Fassero,Lianchun Wang,Dallas R Ederer,Michael A Bierdeman,Eain A Murphy

doi:10.1371/journal.ppat.1009803

Abstract

Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfated glycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell lines deficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, and desulfated heparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.

Highlights

The heparan sulfate (HS) proteoglycans are present on most cell types and function as cellular attachment receptors for medically important viruses, including human immunodeficiency virus (HIV), hepatitis-C virus (HCV), human papillomavirus (HPV), Dengue virus (DENV) and the recently emerged SARS-CoV-2 [1,2,3,4,5,6]
The data suggests that CMV preferentially attaches to uniquely modified HS and this virus-host interaction is amenable to targeting by designed HS mimics
We sought to establish the category of GAG that preferentially binds to purified HCMV virions

Summary

Introduction

The heparan sulfate (HS) proteoglycans are present on most cell types and function as cellular attachment receptors for medically important viruses, including human immunodeficiency virus (HIV), hepatitis-C virus (HCV), human papillomavirus (HPV), Dengue virus (DENV) and the recently emerged SARS-CoV-2 [1,2,3,4,5,6]. Virtually all human herpesviruses, with the possible exception of Epstein Barr virus, use HS as an initial co-receptor for entry [7]. The interaction between cell surface HS and virus envelope is the initial event in the complex process of virus entry. A successful virus entry involves downstream co-receptor interactions leading to fusion between the virus envelope and the cell membrane [8]. In cells, where binding of virus to cell surface receptors induces endocytosis, the usual consequence is the acidification of the endosome, which triggers fusion between the virus envelope and endosomal membrane [7]. Different virus glycoprotein complexes are involved in each case; HS functions as the primary attachment receptor. The presence of HS receptors are well documented in endosomal membranes and HS receptors likely play roles in intracellular virus trafficking [12,13,14,15]

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Discussion

Conclusion