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Herpes Simplex virus type 1 (HSV-1) is an enveloped dsDNA virus of the herpesviridae family that infect oral, and in some cases, genital mucosa and conjunctival epithelia, and later establishes a latent infection in neural ganglia. (Akhtar 2008) (Yoon) Although humans are the only natural host, the virus can infect other species in vitro, indicating a broad distribution of viral receptors and thus, a large host range. (Schelhass)
Cell entry by HSV-1 (outlined in figure 1) is a complex multi-step process that depends upon the consecutive interaction of several viral glycoproteins with various cell surface components. (Schelhass, Spear) Once the initial binding interactions have taken place, HSV-1 enters the cell via pH-independent fusion of the viral and cell lipid membranes. HSV-1 and illustrates the complexities of virus-host cell receptor interactions, due to the large number of viral proteins and receptors required to infect target cells.(Baranowski 2003) This sequence of events is much more complicated than, for example, smaller and simpler RNA viruses, and those that do not possess an envelope and thus not need to initiate membrane fusion.
The envelope of HSV-1 contains at least twelve viral glycoproteins, although only five of these have been implicated in viral entry (Spear 2004)(Ahktar) The first step in viral entry into target cells involves the interaction between heparan sulfate or chondroitin sulfate proteoglycans on the cell surface and the viral envelope glycoproteins gC and gB. Both gC and gB bind to HSPG, but, it is unclear whether gC is truly necessary for HSV-1 infectivity in vitro or whether it simply mediates entry, since studies have shown that viruses deficient in gC may still infect cells, albeit at a lower efficiency. (Herold)(Shukla D & Spear PG, 2001) (Spear 2000) (Akhtar)Additionally, it has been shown that HS is not always necessary in this interaction and it is thought that, in the absence of gC, gB may bind to a co-receptor PILR-Î±, that may mediate binding and possibly even fusion of the viral and cell membranes. (Akhtar 2009) (Herold 1994)(wimmer)
These initial interactions generally take place on filopodia, thin extensions of the plasma membrane, where there is a high concentration of heparan sulfate. The HSV-1 virions then 'surf' towards the cell body by utilising an actin-dependant mechanism. (Fields ch 5) (Akhtar 2008) At the plasma membrane of the cell body, further interactions between HSV glycoproteins gB, gD, gL and gH and cell surface molecules take place. gD has been shown to interact with at least three classes of molecules that act as coreceptors for HSV-1 entry, (summarised in table 2) including three Herpes Virus entry proteins (Hve): HveA, nectin-1 (HveC) and specific sites on heparan sulfate modified 3-O-sulfotransferase (3-OST). The fact that cells expressing gD constitutively from a transgene are resistant to HSV-1 infection highlights the importance of gD in the process of infection. (Campadelli 2000) gD, in concert with gB and the gH-gL heterodimer, mediates the fusion of the viral envelope and cell membrane, creating a pore that allows entry of the viral capsid and tegument proteins.
(spear 2004) (schelhaas)
HSV-1 receptor roles in Tropism and Pathogenesis
HSV-1 has a broad host range due to the wide distribution of HSPG and nectin-1. (Campadelli 2000) Additionally, table 1 illustrates that HSPG acts as an attachment receptor for many viruses other than HSV-1. (Akhtar) However, since the attachment receptor heparan sulfate, recognized by gC or gB, is present on a greater variety of cells than the receptors for gD, the latter appears to be the principal determinant of specific HSV-1 cell tropism. (Akhtar) (spear 2006) 3-O-sulfated heparan sulfate is only located on certain cell types (Table 2). Nectin-1 is generally confined to the adherens junctions of cells, and therefore can only act as an entry receptor when cells are damaged or during cell-cell transmission. (spear 2004) However, studies have shown that binding of gD, by an unknown mechanism, increases the concentration of nectin-1 on the cell surface. (Krummenacher 2003) (Yoon)(feilds) Similar signalling to increase receptor distribution is used by other viruses, such as adenovirus, to increase the concentration of CAR. Nectin-1 is not expressed on motor neurons, while it is expressed highly on sensory neurons. This explains the specific tropism of HSV-1 for sensory neurons. (Mata)
HSV-1 role in cell-cell spread
Two further glycoproteins and their interaction with unidentified receptors are involved in the cell-cell spread of HSV-1 between polarized cells that form cell junctions, such as epithelial cells, fibroblasts and neuronal cells and probably contributes to the and neuroinvasion of the virus from mucosal epithelia. (Digwell 1998) However, this process is not well understood. The heterodimer gE-gI accumulates at cell junctions and the virions bud from the cell. The complex then binds the membrane and, once attached through gE/gI-receptor interactions, the same glycoproteins that mediate extracellular entry of HSV-1 into uninfected cells mediate cell-cell spread. gD is also implicated in this process (diagram) However, gE-gI is not required for extracellular entry of HSV-1 into cells, as described above. Many studies have demonstrated that these proteins are absolutely required for cell-cell transmission (Polcicova 2005)(Campadelli 2000)(Dingwell 1998)
The gE/gI complex also plays an important role in immune evasion. gE/gI binds to the Fc domain of antibodies directed against other viral proteins, sequestering these antibodies and blocking antibody effector function (McGraw 2009) that are concentrated at epithelial cell junctions. gC has also been shown to modulate immune function through binding C3b to inhibit complement activation. (Friedman)
Entry Receptor for gB/gC
Distribution and function
Other viruses that use the same receptor
Broad tissue distribution.
Entry Receptor for gD
Distribution and function
Other viruses that use the same receptor
HveA/HVEM (Herpes Virus Entry Mediator)
Broad tissue distribution, but is prominent in lymphoid tissues, including spleen, peripheral blood, and thymus.
HVEM is a lymphotoxin receptor and a member of the Tumour Necrosis Factor Receptor Family
HSV-1, HSV-2, PrV (porcine and murine HveA),
Nectin-1/HveC/Poliovirus receptor-related protein
Epithelial, fibroblastic, haematopoietic, endothelial and sensory neuronal cells
A member of the Ig superfamily, has roles in cell adhesion, organisation of adherens junctions (web)
HSV-1 HSV-2, BHV-1, PrV.
3-O-sulfated heparan sulfate
Human neuronal and endothelial cells
(Schneider) (Baranowski 2003) (spear 2003)
Nectins are homologous t human PVR (Campadelli 2000)
widely accepted model for membrane fusion suggests
that binding of gD to one of its cognate receptors
induces conformational changes in gD that mobilize a
fusion active multi-glycoprotein complex involving gB,
gD, gH and gL (Fig. 2) .
. In the case of HSV, gB can mediate
the binding of virus to heparan sulfate if gC is absent
(Herold et al., 1994). In the absence of
heparan sulfate and other glycosoaminoglycans to
which virus can bind, entry is very inefficient but can
occur, probably through the interaction of gD with cell
above, gD may not be an essential component of the
membrane-fusing machinery because mutations in the
PRV or BHV-1 genomes can allow infectious virus to be
produced in the absence of gD. However, gD, through its
interaction with a cell surface receptor, apparently provides
the usual trigger for initiating membrane fusion.
potential binding site on gD for
the nectins and provide additional evidence that HVEM and the
nectins bind to different regions of gD (Manoj)
It should be noted that both GAGs and a mediator of entry such as HVEM are required for HSV infection. Cells lacking GAGs are 100-1000 times more resistant to infection. .. Infection of activated T cells.. (Montgomery)
The quartet therefore represents
the minimum requirement for HSV entry and
fusion. gD is the virion component that interacts
with the surface receptors of the target cells, hence
it is the major determinant of the speci¬c HSV
Binding of herpesviruses to HS proteoglycans
likely precedes a conformational change that brings viral gD t
the binding domain of host cell surface gD receptors (29-31).
Thereafter, a concerted action involving gD, its receptor, three
additional HSV glycoproteins (gB, gH, and gL), and possibly
an additional gH coreceptor triggers fusion of the viral envelope with the plasma membrane of host cells (43, 45, 50).
Fig 2. Molecular Interactions that facilitate HSV-1 entry into cells.
Initial cell contact is usually mediated by interaction between heparan sulfate chains on cell surface proteoglycans HSV-1 glycoproteins gC and/or gB. It is unclear whether or not gC is necessary for binding, but the interaction is shown with HSPG in the figure. This interaction generally occurs on filopodia, where there is a high concentration of HSPG. The attached HSV-1 molecule 'surfs' toward the cell body by utilising the cell actin, as indicated by the blue arrow.
gD can then bind to one of three entry receptors (see table 2). The binding of gD to one of these receptos induces membrane fusion (Lipid Mixing), mediated by the interaction between gD, gH-gL and gB with a gD receptor on the cell surface. The nucleocpsid is released into the cell cytoplasm.
Adapted from References - and -- Akhtar 2009 and Shukla and Spear 2001