Ephrin receptor: a door to KSHV infection

Kaposi's sarcoma–associated herpesvirus is a major oncogenic virus that has been implicated in human cancers. A new study identifies ephrin receptor A2 as a key host receptor for this virus that permits infection of endothelial cells (pages 961–966).

Kaposi's sarcoma–associated herpesvirus (KSHV) causes two types of malignancies: the endothelial tumor eponymously named Kaposi's sarcoma and B cell malignancies including multicentric Castleman's disease and primary effusion lymphoma, in which the virus is associated with plasmablastic and pre–terminally differentiated B cells, respectively. Various host factors have been found to facilitate KSHV cell entry and establishment of infection (Box 1). However, given that these molecules are predominantly ubiquitously expressed, it is unclear how the virus is lured specifically to cells of the endothelial lineage.

Cell entry is a fundamental component of the biology of any virus. For enveloped viruses such as herpesviruses, cell entry is a multistep process that involves viral envelope glycoproteins as well as several cellular attachment and entry factors (Fig. 1). The virus envelope proteins have two functions: specific attachment of the virus to the cell and membrane fusion. The KSHV envelope glycoproteins H and L form a dimer (gH-gL) that is necessary for entry into the host cell.

Figure 1: Ephrin signaling and KSHV entry.
figure1

(a) Ephrin-A binding to EphA induces EphA dimerization and phosphorylation, triggering signal transduction pathways, for example, focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K). EphA activation is implicated in actin reorganization and cell motility. In contrast to other RTKs, ligand binding to EphA also induces reverse signaling to cells where the ligand is bound to the cell membrane, activating FYN and other kinases. (b) KSHV glycoproteins, including K8.1 and gB, bind endothelial cells by interacting with heparan sulfate. gB may also engage directly with integrins to induce intracellular signaling. Hahn et al.1 now show that the KSHV glycoprotein complex gH-gL binds EphA2. Glycoprotein binding to this host receptor triggers intracellular signal transduction pathways including activation of FAK, creating an environment that is conducive to viral infection. Virus binding is followed by internalization and virus transport in the cytoplasm by endocytosis and fusion of the viral envelope with the endosomal membranes. Viral capsids released in the cytoplasm are transported to the perinuclear region, where viral genomes are released and enter the nucleus via nuclear pores.

In this issue of Nature Medicine, Hahn et al.1 report that the ephrin receptor A2 (EphA2) tyrosine kinase specifically binds the KSHV attachment glycoproteins gH and gL, allowing virus entry (Fig. 1). The authors showed that EphA2 co-precipitates with gH-gL and with KSHV virions in vitro1. They then performed a number of experiments to provide convincing evidence that this host cellular molecule functions as a receptor for KSHV: knockdown or deletion of EphA2 inhibited or abolished KSHV infection of endothelial cells, and overexpression of EphA2 enhanced infection; preincubating KSHV virions with soluble EphA2 or pretreating endothelial cells with a soluble EphA2 ligand inhibited infection; and binding of KSHV gH-gL to EphA2 activated EphA2 phosphorylation and promoted endocytosis1. This work coincides with the observation that EphA2 is required for KSHV entry and trafficking, but not necessarily for KSHV attachment to target cells2. Together, these results suggest that EphA2 has a crucial role in the infection of endothelial cells by KSHV.

The first Eph receptor was discovered in 1987 in a cancer cell line called erythropoietin-producing hepatocellular3. Eph ligands were dubbed ephrins (Eph receptor–interacting molecules). Ephs are now the largest receptor tyrosine kinase (RTK) family, with 14 known human members. In contrast to most other ligand-RTK interactions that result in activation of the receptor, upon interaction with Eph receptors, membrane-bound ephrins are also activated to produce signals in their host cells, a phenomenon termed reverse signaling, and these signaling pathways can alternately trigger cell repulsion or attraction. In 1998 the focus of research into Ephs moved to vascular development when it was discovered that EphB4 and its ligand, ephrinB2, distinguish veins and arteries, respectively, in the developing vascular bed4. EphA2 was shown to be sufficient to transform mammary epithelial cells, indicating that EphA2 can function as an oncoprotein5. EphA2 is overexpressed in many human cancers, including Kaposi's sarcoma. Blocking EphA2 activation also inhibits angiogenesis in experimental tumor models6. More recently it was shown that EphA3 is commonly mutated in colorectal and lung cancers, where its mutated form is thought to act as a driver of oncogenesis. However, the signaling outcomes of Eph receptors might be difficult to gauge by studying one Eph in isolation, as different Eph receptors aggregate on the cell surface to signal, and this aspect may explain the conflicting reports on their functions in the literature. Relevant to Kaposi's sarcoma biology, EphA2 is expressed by lymphatic endothelial cells, and Eph receptors and ephrins have been implicated in lymphatic development and lymphangiogenesis7,8.

Currently, the downstream signaling cascades activated specifically by the KSHV gH-gL–EphA2 interaction identified by Hahn et al.1 remain unknown. Furthermore, whether KSHV binding of and signaling through EphA2 elicit endothelial cell responses involved in Kaposi's sarcoma development, including migration, recruitment, differentiation or proliferation, will need to be established.

Ephrins and their receptors have also been implicated as cellular entry molecules for other viruses9,10,11. An RNAi kinase screen identified epidermal growth factor receptor and EphA2 as host cofactors for hepatitis C virus (HCV) entry9. These results not only identify RTKs as HCV entry cofactors but also provide promise for exploiting RTKs to prevent viral infection (for example, after liver transplantation for HCV-related pathology) or to treat active HCV infection. EphrinB2 has been found as a cellular receptor for the emerging zoonotic paramyxovirus, Nipah virus10,11. Nipah virus has a broad host range, suggesting that the receptor for this virus is conserved between species. EphrinB2 is expressed on endothelial cells and neurons, which could explain the in vivo tropism of this virus. It has been suggested that ephrinB2 engagement by this virus may act to recruit more endothelial cells to areas of Nipah virus replication. Such a mechanism could also be an attractive hypothesis for why KSHV usurps EphA2 signaling for cell entry.

In contrast to other oncogenic viruses where the respective cancer is associated with integrated or latent viral gene expression (such as human papillomavirus and cervical cancer, Epstein-Barr virus and lymphoma, and human T-lymphotropic virus type 1 and leukemia), there is ongoing lytic KSHV infection present in Kaposi's sarcoma lesions. Targeting lytic viral infection, for example by interfering with infection of endothelial cells, could be a possible therapeutic strategy. Thus, the discovery of EphA2 as a receptor for KSHV provides new insights into Kaposi's sarcoma pathogenesis, opens new avenues for further mechanistic studies and provides potential for translating this finding into clinical practice. As EphA2 has also been implicated directly in angiogenesis and lymphangiogenesis as well as in driving inflammation, processes that are relevant to Kaposi's sarcoma development, targeting this molecule might be an appealing therapeutic option to explore. RTK inhibitors and monoclonal antibodies against Ephs and their ligands are in clinical development as putative therapeutics for cancer. Thus it is hoped that the identification of Ephs and their ligands as receptors for important human pathogens such as KSHV will bolster this area of drug development.

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Boshoff, C. Ephrin receptor: a door to KSHV infection. Nat Med 18, 861–863 (2012). https://doi.org/10.1038/nm.2803

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