Abstract
Cellular Ephrin receptor tyrosine kinases (Ephrin receptors, Ephs) were found to interact efficiently with the gH/gL glycoprotein complex of the rhesus monkey rhadinovirus (RRV). Since EphA2 was recently identified as a receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV) (Hahn et al., Nature Medicine 2012), we analyzed RRV and KSHV in parallel with respect to Eph-binding and Eph-dependent entry. Ten of the 14 Eph proteins, including both A- and B-type, interacted with RRV gH/gL. Two RRV strains with markedly different gH/gL sequences exhibited similar but slightly different binding patterns to Ephs. gH/gL of KSHV displayed high affinity towards EphA2 but substantially weaker binding to only a few other Ephs of the A-type. Productive entry of RRV 26-95 into B cells and into endothelial cells was essentially completely dependent upon Ephs since expression of a GFP reporter cassette from recombinant virus could be blocked to greater than 95% by soluble Eph decoys using these cells. In contrast, entry of RRV into fibroblasts and epithelial cells was independent of Ephs by these same criteria. Even high concentrations and mixtures of soluble Eph decoys were not able to reduce by any appreciable extent the number of fibroblasts and epithelial cells productively entered by RRV. Thus, RRV is similar to its close relative KSHV in the use of Eph family receptors for productive entry into B cells and endothelial cells. However, RRV uses a separate, distinct, Eph-independent pathway for productive entry into fibroblasts and epithelial cells. Whether KSHV also uses an Eph-independent pathway in some circumstances or to some extent remains to be determined.
Highlights
The gamma-2 herpesviruses, called rhadinoviruses, are a distinct subfamily of the lymphotropic herpesviruses
We show that the gH/gL glycoprotein complex of rhesus monkey rhadinovirus binds to and mediates entry of virus into target cells via cellular Ephrin receptor tyrosine kinase proteins
The use of Ephrin receptor tyrosine kinases (Ephs) proteins as receptors is conserved despite substantial sequence variation in gH/gL between two rhesus monkey rhadinovirus (RRV) strain types and between RRV and Kaposi’s sarcoma-associated herpesvirus (KSHV)
Summary
The gamma-2 herpesviruses, called rhadinoviruses, are a distinct subfamily of the lymphotropic herpesviruses. Unlike KSHV, RRV can be grown lytically and to high titer on monolayer cells, principally early passage primary rhesus fibroblasts. Both RRV and KSHV establish persistent infection of B cells in vivo [4,5] and of established B cell lines [6,7]. The B cell appears to be the principal site of persistence of both RRV and KSHV in vivo in their natural hosts [4,5,8]. RRV has been associated with B cell malignancies similar to those caused by KSHV [9,10,11]. While RRV-positive retroperitoneal fibromatosis has been observed in animals inoculated with RRV strain 17577 [10], no tight association of RRV with solid tumors has been reported
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