Abstract
Viruses within a family often vary in their cellular tropism and pathogenicity. In many cases, these variations are due to viruses switching their specificity from one cell surface receptor to another. The structural requirements that underlie such receptor switching are not well understood especially for carbohydrate-binding viruses, as methods capable of structure-specificity studies are only relatively recently being developed for carbohydrates. We have characterized the receptor specificity, structure and infectivity of the human polyomavirus BKPyV, the causative agent of polyomavirus-associated nephropathy, and uncover a molecular switch for binding different carbohydrate receptors. We show that the b-series gangliosides GD3, GD2, GD1b and GT1b all can serve as receptors for BKPyV. The crystal structure of the BKPyV capsid protein VP1 in complex with GD3 reveals contacts with two sialic acid moieties in the receptor, providing a basis for the observed specificity. Comparison with the structure of simian virus 40 (SV40) VP1 bound to ganglioside GM1 identifies the amino acid at position 68 as a determinant of specificity. Mutation of this residue from lysine in BKPyV to serine in SV40 switches the receptor specificity of BKPyV from GD3 to GM1 both in vitro and in cell culture. Our findings highlight the plasticity of viral receptor binding sites and form a template to retarget viruses to different receptors and cell types.
Highlights
Interactions of a virus with receptors on host cells are crucial for viral entry and infection, and determine host range and tissue tropism of the virus
We have analyzed the structural requirements for receptor binding and switching of the human BK polyomavirus (BKPyV), the causative agent of polyomavirus-associated nephropathy
We show that BKPyV uses specific gangliosides that all contain a common a2,8-disialic acid motif to infect cells, and have characterized the interaction in atomic detail
Summary
Interactions of a virus with receptors on host cells are crucial for viral entry and infection, and determine host range and tissue tropism of the virus. Many zoonotic transmissions are based on a virus acquiring binding capability for a new receptor. Despite their importance, most viral specificity switches are poorly characterized, especially for carbohydrate-binding viruses, as methods capable of structure-specificity studies are only being developed for carbohydrates. Other members of the family include Simian Virus 40 (SV40), the human JC Virus (JCPyV), Merkel Cell Polyomavirus (MCPyV) and at least eight other recently discovered human polyomaviruses [1]. BKPyV was first isolated from a kidney transplant recipient in 1971 [2] It establishes a persistent asymptomatic infection in the genitourinary tract of approximately 70% of the adult population [3,4,5]. Complications of BKPyV reactivation include the development of polyomavirus-induced nephropathy (PVN) in kidney transplant recipients, and hemorrhagic cystitis in bone marrow transplant recipients [3,6,7]
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