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Integrin Vβ6 is a high-affinity receptor for coxsackievirus A9

¹ Department of Virology, University of Turku, Kiinamyllynkatu 13, 20520 Turku, Finland
² Department of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK

Correspondence
Outi Heikkilä
outi.lipiainen{at}utu.fi

Coxsackievirus A9 (CAV9), a member of the genus Enterovirus in the family Picornaviridae, possesses an integrin-binding arginine-glycine-aspartic acid (RGD) motif in the C terminus of VP1 capsid protein. CAV9 has been shown to utilize integrins Vβ3 and Vβ6 as primary receptors for cell attachment. While CAV9 RGD-mutants (RGE and RGDdel) are capable of infecting rhabdomyosarcoma (RD) cell line, they grow very poorly in an epithelial lung carcinoma cell line (A549). In this study, the relationships between CAV9 infectivity in A549 and RD cells, receptor expression and integrin binding were analysed. A549 cells were shown to express both integrins Vβ3 and Vβ6, whereas Vβ6 expression was not detected on the RD cells. Native CAV9 but not RGE and RGDdel mutants bound efficiently to immobilized Vβ3 and Vβ6. Adhesion of CAV9 but not RGE/RGDdel to A549 cells was also significantly higher than to RD cells. In contrast, no affinity or adhesion of bacterially produced VP1 proteins to the integrins or to the cells was detected. Function-blocking antibodies against V-integrins blocked CAV9 but not CAV9-RGDdel infectivity, indicating that the viruses use different internalization routes; this may explain the differential infection kinetics of CAV9 and RGDdel. In an affinity assay, soluble Vβ6, but not Vβ3, bound to immobilized CAV9. Similarly, only soluble Vβ6 blocked virus infectivity. These data suggest that CAV9 binding to Vβ6 is a high-affinity interaction, which may indicate its importance in clinical infections; this remains to be determined.