title: The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity.
abstract: The human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidneys of the majority of the population and is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require α2,6-linked sialic acid on the lactoseries tetrasaccharide c (LSTc) glycan for attachment to host cells. In contrast, a JCPyV kidney isolate type 3 strain, WT3, has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and correlated these data with the results of infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement, while the more weakly binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis.
  
  
  OBJECTIVE
  Viral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidneys of the majority of the population and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection.
authors: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
authors: Luisa J
authors: LJ
authors: Ströh
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA.
authors: Melissa S
authors: MS
authors: Maginnis
authors: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
authors: Bärbel S
authors: BS
authors: Blaum
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors: Christian D S
authors: CD
authors: Nelson
authors: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
authors: Ursula
authors: U
authors: Neu
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors: Gretchen V
authors: GV
authors: Gee
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors: Bethany A
authors: BA
authors: O'Hara
authors: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Nasim
authors: N
authors: Motamedi
authors: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Daniel
authors: D
authors: DiMaio
authors: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA walter_atwood@brown.edu thilo.stehle@uni-tuebingen.de.
authors: Walter J
authors: WJ
authors: Atwood
authors: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA walter_atwood@brown.edu thilo.stehle@uni-tuebingen.de.
authors: Thilo
authors: T
authors: Stehle
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007577:JC Virus / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011134:Polysaccharides / Q000378:metabolism*; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism*; D053585:Virus Attachment
chemical_list: D036022:Capsid Proteins; D011134:Polysaccharides; D011991:Receptors, Virus; D012794:Sialic Acids; C581046:glycan sialylneolacto-N-tetraose c