Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Abstract

Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrinbinding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, ␤1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for ␣2␤1, ␣6␤1, and ␣V␤3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.H uman cytomegalovirus (HCMV) is a member of the medically significant Herpesviridae family of viruses. Herpesviruses establish a life-long relationship with their hosts and can manifest disease in an opportunistic manner. HCMV is the most common viral cause of congenital birth defects and is responsible for significant morbidity and mortality in immunocompromised patients, including AIDS patients and organ transplant recipients (1, 2). A notable feature of HCMV pathogenesis is its exceptionally broad tissue tropism. HCMV is capable of manifesting disease in most organ systems and tissue types, which directly correlates with its ability to infect fibroblasts, endothelial cells, epithelial cells, monocytes͞macrophages, smooth muscle cells, stromal cells, neuronal cells, neutrophils, and hepatocytes (3, 4). In vitro entry into target cells is equally promiscuous since HCMV is able to bind, penetrate, and initiate replication in all tested vertebrate cell types (5). HCMV host cell entry begins with a required tethering step to cell surface heparan sulfate proteoglycans (HSPGs) (6). After HSPG binding, the virus transitions to a more stable docking step by engaging unidentified protein receptors (7), all of which lead to fusion at the cell surface (8). Recently, epidermal growth factor receptor (EGFR) was identified as a potential cellular attachment and signaling coreceptor for HCMV, the expression of which correlated with the ability of the virus to initiate gene expression (9). However, EGFR is not expressed on several HCMV permissive cells, such as hematopoetic cell types. Therefore, postattachment entry mediating coreceptors must exist.Many of the physiological consequences associated with HCMV infection are consistent with activation of cellular integrins. Host cel...

Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility

“…1C). This slight induction of PI(3)K and Akt in the presence of either EGFR inhibitor following infection suggests that other HCMV entry receptors, such as integrins (22,23), may also be involved in the activation of the PI(3)K pathway (24). Nonetheless, our results indicate that peripheral blood monocytes express bona fide functional cell surface EGFR.…”

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

“…1). [38][39][40] CD90 has also been linked to HCMV entry, possibly through interaction with HCMV envelope associated glycoproteins. 41 Interestingly, HCMV infection strongly up-regulates expression of PDGFR and CD61, slightly increases CD90 but has no effect on CD29 or EGFR.…”

Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells

“…Although the specific identity of HCMV entry receptor(s) remains to be definitively defined (34)(35)(36), the current model proposes that, upon initial docking to receptor(s), virion fusion and internalization are mediated by interactions with cellular integrins (37, 38) via a DLD within gB (37). In contrast with lytic infection, latent infection is restricted to a subpopulation of CD34 + hematopoietic cells in the bone marrow population (6), particularly the myeloid lineage.…”