Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C

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Abstract
Studies of the recently discovered human rhinovirus species C (HRV-C) virus have been hampered by an inability to propagate the virus in standard cell culture. Yury Bochkov et al. have now developed a tissue culture system for HRV-C using human organ culture of sinus mucosa. This, together with development of a reverse genetics system for HRV-C, should provide a better understanding of HRV-C biology and facilitate discovery of an HRV-C receptor. A recently recognized human rhinovirus species C (HRV-C) is associated with up to half of HRV infections in young children. Here we propagated two HRV-C isolates ex vivo in organ culture of nasal epithelial cells, sequenced a new C15 isolate and developed the first, to our knowledge, reverse genetics system for HRV-C. Using contact points for the known HRV receptors, intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptor (LDLR), inter- and intraspecies footprint analyses predicted a unique cell attachment site for HRV-Cs. Antibodies directed to binding sites for HRV-A and -B failed to inhibit HRV-C attachment, consistent with the alternative receptor footprint. HRV-A and HRV-B infected HeLa and WisL cells but HRV-C did not. However, HRV-C RNA synthesized in vitro and transfected into both cell types resulted in cytopathic effect and recovery of functional virus, indicating that the viral attachment mechanism is a primary distinguishing feature of HRV-C.