Species-Specific Receptor Recognition by a Minor-Group Human Rhinovirus (HRV): HRV Serotype 1A Distinguishes between the Murine and the Human Low-Density Lipoprotein Receptor

Abstract

Human rhinoviruses (HRV) of the minor receptor group use several members of the low-density lipoprotein receptor superfamily for cell entry. These proteins are evolutionarily highly conserved throughout species and are almost ubiquitously expressed. Their common building blocks, cysteine-rich ligand binding repeats about 40 amino acids in length, exhibit considerable sequence similarity. Various numbers of these repeats are present in the different receptors. We here demonstrate that HRV type 1A (HRV1A) replicates in mouse cells without adaptation. Furthermore, although closely related to HRV2, it fails to bind to the human low-density lipoprotein receptor but recognizes the murine protein, whereas HRV2 binds equally well to both homologues. This difference went unnoticed due to the presence of other receptors, such as the low-density lipoprotein receptor-related protein, which allow species-independent attachment. The species specificity of HRV1A reported here will aid in defining amino acid residues establishing the contact between the viral surface and the receptor.Human rhinoviruses (HRVs) constitute a large genus within the family Picornaviridae and are the major cause of common cold infections (for a review on picornaviruses, see reference 43). Their icosahedral capsid is composed of 60 copies each of the viral proteins VP1, VP2, VP3, and VP4. The protein shell encases an RNA genome of positive polarity which is translated into a polyprotein upon arrival in the cytoplasm. The precursor protein is cleaved autocatalytically and cotranslationally by virally encoded proteases, giving rise to the capsid proteins and to the nonstructural proteins involved in replicative functions.Apart from one exception (HRV type 87 [HRV87]), the 102 serotypes are divided into a major and a minor group based on specific interaction with their cellular receptors, intercellular adhesion molecule 1 (ICAM-1; the major group) and members of the low-density lipoprotein receptor (LDLR) family (the minor group). Amino acid sequence information for the entire capsid protein region is available for 11 different serotypes (http://www.iah.bbsrc.ac.uk/virus/picornaviridae /SequenceDatabase/Index.html), and the three-dimensional structures of three major-group and two minor-group serotypes have been solved at atomic resolution (21,38,42,49,54). Medium-resolution structures from complexes of the majorgroup viruses HRV14 and HRV16 with soluble ICAM-1 (22, 39) as well as of the minor-group virus HRV2 and a soluble fragment of the very-low-density lipoprotein receptor (VLDLR) (14) have been obtained by image reconstruction from cryoelectron microscopy data. Whereas ICAM-1 binds inside the canyon, a cleft encircling the fivefold axes of icosahedral symmetry, the HRV2 receptor complex revealed that the BC loop and the HI loop of VP1 were largely covered by two of the three repeats of the recombinant VLDLR fragment VLDLR 1-3 , encompassing ligand binding repeats 1 to 3 only (41).The LDLR family comprises the LDLR proper, VLDLR, LDLR-related protein...

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