THY-1 Cell Surface Antigen (CD90) Has an Important Role in the Initial Stage of Human Cytomegalovirus Infection

Abstract

Human cytomegalovirus (HCMV) infects about 50% of the US population, is the leading infectious cause of birth defects, and is considered the most important infectious agent in transplant recipients. The virus infects many cell types in vivo and in vitro. While previous studies have identified several cellular proteins that may function at early steps of infection in a cell type dependent manner, the mechanism of virus entry is still poorly understood. Using a computational biology approach, correlating gene expression with virus infectivity in 54 cell lines, we identified THY-1 as a putative host determinant for HCMV infection in these cells. With a series of loss-of-function, gain-of-function and protein-protein interaction analyses, we found that THY-1 mediates HCMV infection at the entry step and is important for infection that occurs at a low m.o.i. THY-1 antibody that bound to the cell surface blocked HCMV during the initial 60 minutes of infection in a dose-dependent manner. Down-regulation of THY-1 with siRNA impaired infectivity occurred during the initial 60 minutes of inoculation. Both THY-1 antibody and siRNA inhibited HCMV-induced activation of the PI3-K/Akt pathway required for entry. Soluble THY-1 protein blocked HCMV infection during, but not after, virus internalization. Expression of exogenous THY-1 enhanced entry in cells expressing low levels of the protein. THY-1 interacted with HCMV gB and gH and may form a complex important for entry. However, since gB and gH have previously been shown to interact, it is uncertain if THY-1 directly binds to both of these proteins. Prior observations that THY-1 (a) interacts with αVβ3 integrin and recruits paxillin (implicated in HCMV entry), (b) regulates leukocyte extravasation (critical for HCMV viremia), and (c) is expressed on many cells targeted for HCMV infection including epithelial and endothelial cells, fibroblast, and CD34+/CD38- stem cells, all support a role for THY-1 as an HCMV entry mediator in a cell type dependent manner. THY-1 may function through a complex setting, that would include viral gB and gH, and other cellular factors, thus links virus entry with signaling in host cells that ultimately leads to virus infection.

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

“…[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. HCMV-mediated PDGFR-a expression and activation has been shown to be essential for expression of viral genes, production of viral progeny and activation of signaling cascades.…”

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

“…The involvement of integrins in Kaposi's sarcomaassociated herpesvirus (KSHV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) bolsters the evidence for involvement of these proteins in CMV infection (64)(65)(66)(67)(68). Recently, THY-1 (CD90) was identified as a putative entry factor that may form complexes with CMV gB and gH to link viral entry with signaling events that permit infection (69). A recent study by Wille et al demonstrated that CMV gB expressed on the cell surface could successfully complement infection by virions lacking the gB protein, arguing that gB is involved in fusion and is not required in a receptor-binding role in fibroblasts (70).…”

The Human Cytomegalovirus UL116 Gene Encodes an Envelope Glycoprotein Forming a Complex with gH Independently from gL

“…The more recently discovered gH/gL/ UL128/UL130/UL131A complex (Pentamer) instead is required for endothelial/epithelial cell, leukocyte, and monocyte tropism (26)(27)(28). On the cellular side, several putative HCMV receptors have been described, but none of them completely fulfills the characteristics of an entry receptor (17,29).…”