Introduction

All viruses must deliver their genomes to host cells to initiate infection. The plasma membrane together with cell surface constituents serve as initial barriers to entry as well as the mediators that facilitate the process. This chapter will summarize what is known about the entry pathway of human cytomegalovirus, noting certain parallels and commonalities between human cytomegalovirus (HCMV) and other betaherpesviruses (see Chapter 46 for specific pathways of HHV-6 and HHV-7 entry). The roles of HCMV envelope glycoproteins and cellular receptors that control virion attachment and membrane fusion will be summarized. This chapter will also discuss the emerging role of signaling pathways in the early events in infection and examine how virus entry and innate immune activation may be coordinated.

In the simplest context, entry requires that enveloped viruses, including HCMV, HHV-6A or B and HHV-7, use virion envelope proteins to facilitate adherence to the cell surface and fusion between the virus envelope and a cellular membrane that results in the deposition of virion components into the cytoplasm. Following delivery to the cytoplasm, capsid or tegument proteins facilitate transport through the cytoplasm to and delivery of the viral genome to the nucleus in a process known as uncoating. Tegument proteins also translocate independent of the capsid to cytoplasmic or nuclear sites. For structurally complex viruses whose envelopes contain as many as 20 proteins and glycoproteins, attachment is a multi-step process typically involving more than one envelope glycoprotein interacting with a series of cell surface receptors that serve as primary receptors and coreceptors. One consequence of these virus-cell interactions based largely on information from negative strand RNA viruses is that predicted receptor-activated conformational changes in envelope glycoproteins play roles in membrane fusion. Multiple HCMV envelope glycoproteins are required to fuse membranes. Another consequence of these initial virus–host interactions may be the formation and/or delivery of bound virions to specialized membrane domains or compartments that are optimal for fusion and for activation of signal transduction into the cell. We have also recently learned that HCMV entry is accompanied by innate immune activation. This considerably heightens the complexity of the molecular events occurring during the early events in HCMV infection.

To begin a discussion of virus entry at the cellular level, one must first consider the basis of cellular tropism since receptors involved in entry are expressed on permissive cells. In the human host, HCMV causes systemic infection and exhibits a tropism for fibroblasts, endothelial cells, epithelial cells, monocytes/macrophages, smooth muscle cells, stromal cells, neuronal cells, neutrophils, and hepatocytes (Myerson et al., 1984; Sinzger et al., 2000). This exceptionally broad cellular tropism in the infected host is the basis of HCMV disease manifestation by this opportunist in a variety of organ systems and tissue types in the immunocompromised host. HCMV is considered to have a restricted cell tropism in vitro, however, entry into target cells is very promiscuous, since HCMV is able to bind, fuse and initiate replication in all tested vertebrate cell types. Productive in vitro replication is supported by primary fibroblast, endothelial and certain differentiated myeloid cells as well as some astrocytoma lines (Ibanez et al., 1991; Nowlin et al., 1991). The ability of HCMV to enter such a wide range of cells is consistent with either one broad common receptor or a number of cell-specific multiple cell specific receptors or a complex entry pathway in which a combination of both cell specific and broadly expressed cellular receptors are utilized. By contrast, both major variants of HHV-6 and HHV-7 are predominately T-lymphotropic although HHV-6 can infect certain cells of myeloid lineage as well. HHV-7 uses CD4, a strictly T-lymphocyte expressed molecule as a receptor while HHV-6A and B use a more broadly distributed molecule CD46 as a receptor (Lusso et al., 1994; Santoro et al., 1999).

Cellular receptors for HCMV

It has been known for some time that HCMV initiates infection by binding to cell surface heparan sulfate proteoglycans (HSPGs) (Compton et al., 1991). Engagement of HSPGs is one relatively conserved feature of herpesvirus entry pathways and is also thought to play a role in HHV-6 and HHV-7 interactions with lymphoid cells (Conti et al., 2000). At least in cell culture systems, HCMV engagement of HSPGs is thought to play a crucial role in initial stage of entry by enhancing the engagement of subsequent receptors in a cascade that ultimately leads to fusion (Compton et al., 1993). This hypothesis is further supported by biochemical analysis of HCMV binding, which indicates biphasic binding properties with multiple distinct affinities (Boyle and Compton, 1998).

The ability of HCMV to bind a broad range of cell types in culture has hampered efforts to identify cellular receptors using modern molecular approaches such as expression cloning. Over the past 20 years, numerous receptor candidates have been proposed, but none has been found to be absolutely necessary for infection of all susceptible cell types. These candidate receptor molecules have been selected on the basis of solid initial criteria but none have turned out to be a general entry mediator following further investigation. It is possible that each is important only in certain cell types or tissues. It also remains possible that functional redundancy masks their individual roles.

HCMV virions were initially shown to bind β₂ microglobulin (β₂m) in urine samples (Grundy et al., 1988; McKeating et al., 1987; McKeating et al., 1986). This observation led to binding studies showing that HCMV tegument, not envelope, binds β₂m during release from cells (Grundy et al., 1987a,b; McKeating et al., 1987; Stannard, 1989). This β₂m–HCMV complex was then thought to associate with the alpha chain of host cell major histocompatibility complex (MHC) class Ⅰ antigens (Beersma et al., 1990; 1991; Browne et al., 1990; Grundy et al., 1987a,b). These data led to a model in which β₂m-coated HCMV bound MHC class Ⅰ molecules, displacing β₂m. However, it was later determined that β₂m expression had no correlation with in vitro entry of HCMV or in vivo spread of MCMV infectivity (Beersma et al., 1991; Polic et al., 1996; Wu et al., 1994). The demonstration that β₂m-deficient and MHC class Ⅰ-deficient mice maintain full susceptiblity to MCMV infection (Polic et al., 1996) provided the last piece of evidence confounding this hypothesis.

Virus-cell overlay blots identified a cell surface protein of approximately 30 kDa whose expression correlated with cells permissive for entry, suggesting that this cellular protein may be involved in HCMV entry (Nowlin et al., 1991; Taylor and Cooper, 1990). This protein was later identified as annexin Ⅱ, a protein that normally binds phospholipids and calcium and has membrane bridging capabilities (Wright et al., 1993, 1995). Annexin Ⅱ found associated with HCMV virions (Wright et al., 1994, 1995). Although annexin Ⅱ binds gB and enhances HCMV binding and fusion to phospholipid-containing membranes (Pietropaolo and Compton, 1997; Raynor et al., 1999), cells devoid of annexin Ⅱ are fully permissive for entry and initiation of infection (Pietropaolo and Compton, 1999). The role, if any, for annexin Ⅱ in HCMV entry remains unknown but this protein’s membrane bridging activity may enhance entry, cell–cell spread and/or maturation and egress.

CD13, or human aminopeptidase N, is a glycosylphosphatidylinositol-linked membrane protein that has also been implicated as a receptor. This hypothesis was based on that fact only human peripheral blood mononuclear cells (PBMCs) that were CD13 positive supported productive infection (Larsson et al., 1998; Soderberg et al., 1993a,b). This led to a more thorough study of this possibility in which CD13-specific antibodies, and chemical inhibitors of CD13 activity were both shown to inhibit HCMV binding and entry (Soderberg et al., 1993a). Excitement from this report was dampened by later reports that CD13 antibodies bind to and neutralize virus before contact with cells and by the fact that entry of HCMV into CD13 depleted cells remains normal (Giugni et al., 1996). More recently, an interaction between HCMV and CD13 was shown to be important in inhibition of differentiation of monocytes into macrophages suggesting this may be a strategy for interference with cellular differentiation pathways (Gredmark et al., 2004).

A consideration of HCMV-induced signaling cascades led Huang and colleagues to hypothesize a role for epidermal growth factor receptor (EGFR) as a HCMV receptor (Wang et al., 2003). EGFR was reported to be phosphorylated in response to HCMV and this phosphorylation event correlated with the activation of phosphatidylinositol 3-kinase (PI-3 kinase) and Akt, as well as the mobilization of intracellular Ca²⁺. These signaling events were blocked in the presence of EGFR antibodies. In addition, chemically cross-linked virus provided evidence for a gB–EGFR interaction. A limitation of the study, however was that there was no experimental evidence that EGFR functioned in entry per se nor was it determined whether EGFR was required for the delivery of virion components across the plasma membrane. Also, conflicting results exist in the literature. Fairley and colleagues demonstrated that HCMV promoted inactivation of EGFR phosphorylation and signaling (Fairley et al., 2002). In these experiments, EGFR polyclonal antibodies had no effect on HCMV entry (Soderberg et al., 1993a). It is important to note that EGFR is not expressed on all HCMV susceptible cells, such as those of a hematopoeitic lineage.

Finally, an anti-idiotype antibody to viral envelope glycoprotein H (gH), identified a phosphorylated 92.5kDa cell surface glycoprotein that may be involved in the steps that follow attachment (Keay and Baldwin, 1991, 1992, 1996; Keay et al., 1989, 1995). Combined, the study of HCMV entry receptors, like studies aimed at identifying entry mediators in other herpesviruses, include reports that cannot be reconciled with the ability of this virus to enter and uncoat in a broad range of cell types without invoking functional redundancy. There is continued need for data confirmation as well as further functional investigation of all receptor candidates.

Entry activated cell signaling

The first and foremost observation about HCMV biology was its namesake characteristic, cytomegaly, or cell enlargement. In vitro studies initially demonstrated a unique cytopathogenic effect (CPE) of infected cells, with HCMV infected cells appearing rounded and developing an enlarged appearance with both intracellular and intranuclear inclusion bodies late during infection (Albrecht and Weller, 1980). Infection proceeded with two waves of cell rounding, the first beginning as early as a few hours postinfection and corresponding to the impact of entry, and another starting at approximately 24 hours postinfection, when there is a distinct peak in cellular transcription and translation. The cause of this phenomenon was widely speculated upon however, and theories for HCMV-induced cell rounding included cation influx, suppression of fibronectin synthesis and integrin down-regulation (Albrecht et al., 1983; Albrecht and Weller, 1980; Ihara et al., 1982; Warren et al., 1994).

It has been apparent for many years that cells respond to HCMV virions by activation of numerous cell signaling pathways including changes in Ca²⁺ homeostasis, activation of phospholipases C and A2, as well as increased release of arachidonic acid and its metabolites (for review, see Fortunato et al., 2000). All of these changes can be triggered by UV-inactivated virions (Boldogh et al., 1990, 1991b), suggesting that structural components of the virus are responsible for activation during virus-cell contact and/or virus entry. Virus–cell contact also results in the activation of transcription factors such as cfos/jun, myc, NF-κB, SP-1, as well as phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein (MAP) kinases ERK1/2 and p38 (Boyle et al., 1999; Kowalik et al., 1993; Yurochko et al., 1995, 1997; Boldogh et al., 1991a; Johnson et al., 2001)). These virally induced cellular physiological changes are associated with a profound effect on host cell gene expression. The levels of hundreds of host cell transcripts are altered within a few hours after exposure to virus, virus particles or soluble gB (Browne et al., 2001; Simmen et al., 2001; Zhu et al., 1998). Thus, transcriptional changes immediately after infection do not reflect viral gene expression. These data are consistent with the interpretation that HCMV engages a cellular receptor(s) that activate signal transduction pathways culminating in reprogramming of cellular transcription.

Cellular integrins may serve as coreceptors for betaherpesviruses

Cellular integrins are ubiquitously expressed cell surface receptors that, when activated, lead to major reorganization of the cytoskeleton. Integrins exist on the plasma membrane as non-covalently linked heterodimers consisting of an α- and a β-subunit, which convey specificity in cell–cell and cell–ECM (extracellular matrix) attachment, immune cell recruitment, extravasation, and signaling (Berman and Kozlova, 2000; Berman et al., 2003; Cary et al., 1999). In addition, integrins have emerged as receptors for a broad range of pathogens and mediate binding of plant spores, bacteria and viruses. Feire et al. (2004) investigated the role that integrins play in the HCMV entry pathway. Analysis of the effects of various neutralizing antibodies implicated α2β1, α6β1, and αVβ3 integrins in entry (Feire et al., 2004). Furthermore, cells devoid of β1 integrin exhibited dramatically reduced susceptibility to infection with HCMV or MCMV while entry and spread were restored when the expression of β1 integrin was re-introduced into cells. Integrin-blocking antibodies did not prevent virus attachment but specifically inhibited the delivery of a virion component, pp65, into cells suggesting that integrins function at a post-attachment stage of infection, possibly at the level of membrane fusion. The involvement of multiple integrin heterodimers is consistent with integrin biology in that many natural integrin ligands, such as extracellular matrix proteins, bind to a variety of heterodimers. Furthermore, other integrin-binding viruses are characterizd by binding to a number of different integrin heterodimers (Stewart et al., 2003).

Integrins are capable of engaging ligands through a number of identified ECM protein motifs, the most common of which contain the amino acid sequence RGD. However, there are a number of RGD-independent integrin binding motifs, including the disintegrin domain proteins of the A Disintegrin and A Metalloprotease (ADAM) family of proteins. After inspection of all HCMV structural glycoproteins, the strongest homology to an integrin-binding domain was a disintegrin-like consensus sequence (RX_5–7 DLXXF/L) (Eto et al., 2002; Stone et al., 1999; Wolfsberg et al., 1995) on the amino-terminus of gB. Sequence alignments confirmed that the gB disintegrin loop was more than 98% identical among 44 clinical isolates analyzed. The role of this sequence in entry was confirmed through the use of synthetic peptides that inhibited both HCMV and MCMV entry, but had no impact on entry of HSV, correlating with the lack of a disintegrin-loop in gB of this virus. Furthermore, the HCMV gB disintegrin-loop was conserved throughout much of the gamma and all of the betaherpesvirus subfamilies, but not in the alphaherpesvirus subfamily where previously identified RGD sequences appear to carry out interactions with integrins. The presence of integrin-binding sequences among conserved herpesvirus glycoproteins strongly suggests that integrins may be important for entry and signaling throughout this medically important family. EGFR has also been shown to become phosphorylated and signal indirectly, as a result of integrin activation through src family kinases or focal adhesion kinase (FAK) (Jones et al., 1997; Miyamoto et al., 1996; Moro et al., 1998). Future work will no doubt be aimed at an analysis of the integrin-triggered signaling events and defining their roles in entry and infection.

Activation of innate immunity during entry

The cellular response to HCMV particles includes dramatic upregulation of interferon stimulated genes, including interferon β itself and inflammatory cytokines; indicators of host innate immunity (Browne et al., 2001; Simmen et al., 2001; Zhu et al., 1998; Yurochko and Huang, 1999). Toll-like receptors (TLRs) are ancient, conserved, pathogen sensors now well appreciated to activate signal transduction pathways that lead to induction of antimicrobial/antiviral genes and inflammatory cytokines (Akira, 2001). Until recently, however, TLRs were not known to recognize virus particles. To date, members of the herpesvirus, retrovirus and paramyxovirus families have been shown to be subject to innate sensing by TLRs (Compton et al., 2003; Haynes et al., 2001; Kurt-Jones et al., 2000; Rassa et al., 2002). In particular, TLR2 on PBMCs recognize HCMV particles or virus in a comparable manner, suggesting that binding and/or entry events involve the activation of this receptor. Soluble gB is able to induce a similar pattern of innate immune gene expression and can induce an antiviral state in cells (Boehme et al., 2004; Boyle, Pietropaolo and Compton, 1999). Another envelope glycoprotein (gH) activates cells (Yurochko et al., 1997) and the gH/gl/gO complex may contribute to a pattern of innate immune activation as a component of entry (Netterwald et al., 2004), Guerrero M. and T. Compton, unpublished observations). TLR2 stimulation results in activation of NF-κB and stimulation of inflammatory cytokine production (Compton et al., 2003). A common theme has emerged implicating viral envelope glycoprotein as a specific molecular trigger for TLR activation and that viral gene expression is not required (Boehme and Compton, 2004). These studies suggest a heretofore-unknown host cell response that detects viruses during entry, prior to the onset of replication events and products such as double stranded RNA that have long been recognized as TLR ligands (Boehme and Compton, 2004). Innate sensing of viruses during entry does not result in signaling that is essential to viral replication and appears more important as a determinant of the host cell response. The interaction of envelope glycoprotein and TLR suggests that entry and innate sensing may be coordinated in some manner.

Roles of betaherpesvirus envelope glycoproteins in virus entry

The HCMV envelope is exceedingly complex and currently incompletely defined. The HCMV genome encodes ORFs to at least 57 putative glycoproteins; far more than other herpesviruses, however, the extent of transcription, translation and function of the majority of these glycoproteins remains unknown. Biochemical studies of HCMV virions have revealed that 14 structural glycoproteins; eight of which have been experimentally shown to reside in the envelope (Britt et al., 2004). HCMV appears to rely on herpesvirus-common homologues for entry. These include herpesvirus-common gene products gB and gH as well as glycoproteins L (gL), O (gO), M (gM), and N (gN). A number of other structural glycoproteins (gpTRL10, gpTRL11, gpTRL12 and gpUL132, gpUS28) are HCMV-specific (Table 16.1) but so far have no role in entry.

Table 16.1

Envelope proteins of CMV.

For years, the large genome and complicated reverse genetics system have made the creation of HCMV knockout and mutant viruses difficult. Recently, a system capable of such mutations was developed whereby HCMV is maintained as an infectious bacterial artificial chromosome (BAC) within Escherichia coli (Borst et al., 1999). This development has greatly hastened the process of mutating individual ORFs and will generate much information regarding both the structure and function of many envelope glycoproteins. In fact, the BAC system has demonstrated the requirement for several glycoprotein genes in the production of replication competent virus (Dunn et al., 2003; Hobom et al., 2000; Yu et al., 2002). The HCMV glycoprotein homologues gB, gM, gN, gH, gL, have been shown to be essential for growth, while gO knockout virus remained viable with a small plaque phenotype (Hobom et al., 2000). Genes for all the currently identified HCMV-specific envelope glycoproteins, including UL4 (gp48), TRL10 (gpTRL10), TRL11 (gpTRL11), TRL12 (gpTRL12), US27, UL33, UL132, have been shown to be dispensable for replication and therefore are not critical for entry (Dunn et al., 2003). The HCMV-encoded chemokine receptor US28 is present in the virion envelope and has been shown to promote cell–cell fusion mediated by HIV and VSV viral proteins, however the gene has been shown to be non-essential and there is no evidence for a role for gpUS28 in either HCMV–cell or cell–cell fusion events (Dunn et al., 2003; Pleskoff et al., 1997, 1998).

Essential and abundant HCMV envelope glycoproteins conserved throughout the herpesviruses (including gB and gH:gL) were classified as distinct disulfide-linked high molecular weight complexes (gCI and gCIII) in HCMV-infected cells (Gretch et al., 1988). The gCI complex is composed of homodimers of gB (Britt, 1984; Britt and Auger, 1986) and the gCIII complex is a heterotrimeric complex composed of gH, gL, and gO (Huber and Compton, 1997, 1998; Li et al., 1997). The designation gCII has been applied to a heterodimeric complex composed of gM and gN (Mach et al., 2000).

At least two glycoprotein complexes have heparan sulfate proteoglycan (HSPG) binding ability, gB and the gM component of the gM:gN complex, suggesting a critical role for cell surface proteoglycan in initial virus:cell contact (Carlson et al., 1997; Kari and Gehrz, 1993). Heparin binding is a property that HCMV shares with other herpesviruses, and gB is the common glycoprotein involved in this activity. HCMV gB also appears to be the primary receptor binding protein. Soluble forms of gB exhibit biphasic binding properties and cells treated with gB are refractory to infection suggesting that gB ties up critical receptor sites used by the virus (Boyle and Compton, 1998). One of the binding sites for gB is HSPGs in that cells lacking HSPGs had a single component Scatchard plot as compared to a biphasic plot for HSPG bearing cells. As noted above, it now seems clear that a second binding partner is an integrin (Feire et al., 2004) but much work remains to formally prove the disintegrin hypothesis and confirm the role of this domain in receptor engagement. The gB protein may also engage EGFR (Wang et al., 2003), at least in certain cell types, however it is not yet known if this interaction requires initial interaction with integrin. The gH complex may also have a distinct receptor. Syngeneic monoclonal anti-idiotypic antibodies were created that bear the “Image” of this glycoprotein complex (Keay et al., 1988) and led to a putative gH receptor (Keay and Baldwin, 1989, 1991, 1992, 1996). These investigations relied heavily on a single reagent (anti-idiotypic antibodies) and has led to only a partially sequenced receptor clone, lacking homology to known human proteins (Baldwin et al., 2000; Keay and Baldwin, 1996). Thus, the identity of a HCMV gH/gL/gO receptor remains unknown. Since HCMV gH and gL are essential and infectivity can be neutralized with gH antibodies, anti-idiotypic antibodies can neutralize infectivity and the closest relative of HCMV, HHV-6, contains an analogous complex consisting of the herpesvirus-common gH and gL with the product of U100 (gQ), a complex that has been shown to interact with a candidate receptor (Santoro et al., 1999). HHV-6 U47 is the homolog of HCMV UL74 (gO), and is also involved in complex formation.

Membrane fusion remains a poorly understood component of entry for any of the herpesviruses. Unlike orthomyxoviruses, paramyxoviruses, filoviruses and retroviruses that employ a single envelope glycoprotein for membrane fusion, herpesviruses appear to employ multicomponent fusion machines, with evidence that these consist of gB, gH and gL (Spear and Longnecker, 2003). Both the HCMV gB- and gH-dependent entry processes are susceptible to inhibition by neutralizing antibodies that block infection at a postattachment stage of entry, presumably at the level fusion (Bold et al., 1996; Britt, 1984; Keay and Baldwin, 1991; Tugizov et al., 1994; Utz et al., 1989). One limitation of these conclusions, however, is the lack of a direct fusion assay and thus a role for these glycoproteins in fusion is inferred. Despite the complexity of multicomponent fusion machines, it is very likely that there are strong parallels to single component fusion proteins. Alpha helical coiled-coils critical structural domains involved in fusion that function to drive the energetic folding of membranes together. Conformational changes in fusogenic proteins bearing these coiled-coils are also a defining paradigm. Using an algorithm to detect potential structural motifs, Lopper and Compton identified heptad repeat regions in gB and gH that were predicted to form alpha helical coiled coils (Lopper and Compton, 2004). Synthetic peptides to these motifs substantially inhibit HCMV entry including virion content delivery suggesting that these motifs play a fundamental role in membrane fusion. Genetic analysis of these motifs in the context of HCMV virions will be required to further analyze the importance of alpha helical coiled coils in HCMV entry. Another fundamental question will be to determine if the gB integrin interaction is a trigger of conformational change that leads to exposure of membrane fusion domains. Intriguingly, disintegrin-bearing cellular proteins in the ADAM family are known to trigger fusion via integrin interaction in a variety of processes including sperm–egg fusion and myoblast fusion (White, 2003). Development of a reliable fusion assay is also greatly needed to begin a dissection of the biophysical properties of HCMV fusion glycoproteins.

Coordination of entry and innate immune activation

We are left with an apparent dichotomy. As HCMV enters cells to establish infection, the host recognizes the virions and activates innate immune responses. How are the two processes coordinated, or are they coordinated at all? At this time, there is no apparent role for TLRs in entry in that cell stimulation that follows this event does not contribute to replication efficiency in any observable way. It seems more likely that this is a component of the entry process where the host cell senses a pathogen-associated molecular pattern displayed on HCMV envelope glycoproteins and uses this activatation to initiate a host innate defense response. One possibility is that entry receptors such as EGFR, integrins and signaling machinery, and innate immunity sensors such as TRLs, cytoplasmic adaptors and signaling machinery, coalesce into specialized membrane microdomains with integrins playing a central ligating role. Concentration of all of these cell surface receptors into a defined platform likely facilitates cell signaling events, some of which are optimal for replication and others of which are clearly hostile to the virus. Intriguingly integrins associate with TLR2 and partition into cholesterol rich lipid rafts (Ogawa et al., 2002; Triantafilou et al., 2002). The complexity of events at the cell surface during the initial encounter of HCMV and cells represents an exciting opportunity to better understand the molecular underpinnings of the early virus-host interactions. The recent identification of cell surface molecules involved in the early steps in infection has greatly enhanced our knowledge of entry events in infection. Yet much remains to be done to elucidate aspects of mechanism of entry events and the corresponding innate immune activation.

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