Mutations in the GM1 Binding Site of Simian Virus 40 VP1 Alter Receptor Usage and Cell Tropism

Magaldi, Thomas G.; Buch, Michael H. C.; Murata, Haruhiko; Erickson, Kimberly D.; Neu, Ursula; Garcea, Robert L.; Peden, Keith; Stehle, Thilo; DiMaio, Daniel

doi:10.1128/jvi.00371-12

Cited by 27 publications

(43 citation statements)

References 53 publications

(71 reference statements)

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“…This contrasts with our previous data showing that BKV-IV cannot efficiently transduce ganglioside-deficient Chinese hamster ovary (CHO) cells unless GT1b is added exogenously (33). To examine whether BKV-IV can transduce cell lines other than GM95 via a ganglioside-independent pathway, we performed a series of experiments in which ganglioside expression was knocked down on human A549 or ART cells using short interfering RNA targeting GM3 synthase (34). The results showed that GM3 synthase knockdown inhibited BKV-IV transduction (data posted at http://home .ccr.cancer.gov/Lco/BKV.asp).…”

Section: Fig 2 Bkv-neutralizing Titers Of Human Seracontrasting

confidence: 39%

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Pastrana

Ray

Magaldi

et al. 2013

J Virol

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BK polyomavirus (BKV) causes significant urinary tract pathogenesis in immunosuppressed individuals, including kidney and bone marrow transplant recipients. It is currently unclear whether BKV-neutralizing antibodies can moderate or prevent BKV disease. We developed reporter pseudoviruses based on seven divergent BKV isolates and performed neutralization assays on sera from healthy human subjects. The results demonstrate that BKV genotypes I, II, III, and IV are fully distinct serotypes. While nearly all healthy subjects had BKV genotype I-neutralizing antibodies, a majority of subjects did not detectably neutralize genotype III or IV. Surprisingly, BKV subgenotypes Ib1 and Ib2 can behave as fully distinct serotypes. This difference is governed by as few as two residues adjacent to the cellular glycan receptor-binding site on the virion surface. Serological analysis of mice given virus-like particle (VLP)-based BKV vaccines confirmed these findings. Mice administered a multivalent VLP vaccine showed high-titer serum antibody responses that potently cross-neutralized all tested BKV genotypes. Interestingly, each of the neutralization serotypes bound a distinct spectrum of cell surface receptors, suggesting a possible connection between escape from recognition by neutralizing antibodies and cellular attachment mechanisms. The finding implies that different BKV genotypes have different cellular tropisms and pathogenic potentials in vivo. Individuals who are infected with one BKV serotype may remain humorally vulnerable to other BKV serotypes after implementation of T cell immunosuppression. Thus, prevaccinating organ transplant recipients with a multivalent BKV VLP vaccine might reduce the risk of developing posttransplant BKV disease. BK polyomaviruses (BKVs or BKPyVs) are a species of icosahedral, nonenveloped, double-stranded DNA viruses. The genomes of all known full-length isolates of BKV can be categorized into four discrete genotypes based on analyses of nucleotide sequences (1). The prevalence and sequence characteristics of each genotype are thought to vary within different human populations worldwide (2).Studies indicate that 83 to 98% of individuals show serum antibody responses to the BKV genotype I (BKV-I) major capsid protein, VP1, by the time they are 21 years of age (3). The virus is thought to establish a lifelong chronic infection in the urinary epithelium, and virions are periodically shed at low levels in the urine of 5 to 27% of healthy adults (4, 5). Although BKV-I can cause malignancy in animal model systems, conclusive evidence showing a causal connection between BKVs and human cancer is still lacking (reviewed in reference 6). While it remains uncertain whether BKVs cause pathology in healthy individuals, it is clear that certain T cell-immunosuppressed individuals, such as recipients of kidney or bone marrow transplants, are at risk of developing uncontrolled BKV replication that leads to nephropathy or hemorrhagic cystitis, respectively (reviewed in reference 7). Currently available antiv...

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Section: Fig 2 Bkv-neutralizing Titers Of Human Seracontrasting

confidence: 39%

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Pastrana

Ray

Magaldi

et al. 2013

J Virol

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“…To determine whether JCPyV is able to utilize gangliosides as functional receptors for infection, SVGA cells were supplemented with a panel of gangliosides prior to infection with JCPyV Mad-1, Mad-1/WT3C, BKPyV, and SV40. BKPyV utilizes the gangliosides GD1b and GT1b as functional receptors, while SV40 utilizes GM1, and exogenous ganglioside addition has been previously demonstrated to enhance infection (25,59). Interestingly, supplementation of cells with gangliosides GM1, GM2, GD1a, GD1b, and GT1b did not alter JCPyV infection compared to that for the dimethyl sulfoxide (DMSO)-treated control.…”

Section: Exogenous Addition Of Gangliosides Does Not Enhance Jcpyv Inmentioning

confidence: 89%

“…7B), indicating that both strains of JCPyV require 5-HT 2 Rs for productive infection. In contrast, BKPyV and SV40 can still switch their glycan receptor specificity through a single VP1 point mutation, but these viruses both utilize lipid-linked ganglioside receptors and share a cholesterol-dependent entry mechanism (25,59). Binding of JCPyV to LSTc may induce organizational and/or structural changes at the plasma membrane that favor interactions with the entry receptor 5-HT 2 R.…”

Section: Discussionmentioning

confidence: 99%

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

Stroh

Maginnis

Blaum

et al. 2015

J Virol

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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 ␣2,6-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. IMPORTANCEViral 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. J C polyomavirus (JCPyV) infects ϳ50% of healthy individuals and causes an asymptomatic, lifelong persistent infection in the kidney (1, 2). The form of the virus that resides in the kidney is nonpathogenic and is excreted in the urine (3, 4). In immunosuppressed individuals, JCPyV can spread from the site of persistence to the central nervous system (CNS) (5, 6) and infect the glial cells astrocytes and oligodendroctyes (7,8). Oligod...

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“…SV40, which is closely related to BKV and JCV, is known to require the sialylated ganglioside GM1 for infectious entry into many (but not all) cell types (Magaldi et al, 2012). Prior work has not addressed the possibility that GAGs might be involved in SV40 infectious entry.…”

Section: Resultsmentioning

confidence: 99%

Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

et al. 2017

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Summary Progressive multifocal leukoencephalopathy (PML) is a lethal brain disease caused by uncontrolled replication of JC polyomavirus (JCV). JCV strains recovered from the brains of PML patients carry mutations that prevent the engagement of sialylated glycans, which are thought to serve as receptors for the infectious entry of wild-type JCV. In this report, we show that non-sialylated glycosaminoglycans (GAGs) can serve as alternative attachment receptors for the infectious entry of both wild-type and PML-mutant JCV strains. After GAG-mediated attachment, PML-mutant strains engage non-sialylated non-GAG co-receptor glycans, such as asialo-GM1. JCV-neutralizing monoclonal antibodies isolated from patients who recovered from PML appear to block infection by preventing the docking of post-attachment co-receptor glycans in an apical pocket of the JCV major capsid protein. Identification of the GAG-dependent/sialylated glycan-independent alternative entry pathway should facilitate the development of infection inhibitors, including recombinant neutralizing antibodies.

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Mutations in the GM1 Binding Site of Simian Virus 40 VP1 Alter Receptor Usage and Cell Tropism

Cited by 27 publications

References 53 publications

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

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

Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

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