New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America.
PLoS Pathog. 2013;9(5):e1003360. doi: 10.1371/journal.ppat.1003360. Epub 2013 May 16.
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.
细胞表皮生长因子受体酪氨酸激酶（Eph 受体，Ephs）被发现可与恒河猴疱疹病毒（RRV）的 gH/gL 糖蛋白复合物有效相互作用。由于 EphA2 最近被鉴定为卡波济肉瘤相关疱疹病毒（KSHV）的受体（Hahn 等人，《自然医学》2012 年），我们分析了 RRV 和 KSHV 在 Eph 结合和 Eph 依赖性进入方面的平行关系。14 种 Eph 蛋白中的 10 种，包括 A 型和 B 型，都与 RRV gH/gL 相互作用。两种 RRV 株的 gH/gL 序列差异明显，但与 Eph 的结合模式相似但略有不同。KSHV 的 gH/gL 对 EphA2 具有高亲和力，但对 A 型的其他少数几个 Eph 的结合能力要弱得多。RRV 26-95 进入 B 细胞和内皮细胞的有效进入基本上完全依赖 Eph，因为使用这些细胞的可溶性 Eph 诱饵可以将重组病毒的 GFP 报告基因盒的表达阻断超过 95%。相比之下，根据这些标准，RRV 进入成纤维细胞和上皮细胞与 Eph 无关。即使高浓度和可溶性 Eph 诱饵混合物也不能在任何可察觉的程度上减少 RRV 有效进入的成纤维细胞和上皮细胞的数量。因此，RRV 与其近亲 KSHV 相似，可利用 Eph 家族受体有效进入 B 细胞和内皮细胞。然而，RRV 使用一种单独的、不同的、Eph 独立的途径来有效进入成纤维细胞和上皮细胞。KSHV 是否在某些情况下或在某种程度上也使用 Eph 独立途径仍有待确定。
