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Herpes simplex virus (HSV), a neurotropic DNA virus has many
advantageous properties as a gene delivery vector, just like all viruses HSV
also exhibits a natural tropism for specific cell types within the body. HSV
has the ability to infect almost every cell in the body, thus beneficial to retarget
virus infectivity in order to accomplish selective target cell infection. A method known as retargeting can be performed
to ensure the delivery of the viral vector to the intended cell or tissue. This
limits viral vector infection to only the desired target cell.  


An array of retargeting
studies over the years have significantly enhanced the understanding of HSV
entry. This ultimately led to the development of fully retargeted HSV vectors.  Retargeting can be performed to either expand or
restrict the tropism of viruses that affect a number of cell types. However, unlike
other enveloped viruses such as HIV and influenza which use one or more
glycoproteins to bind and enter host cells, HSV or members of the herpesvirus
family rely on a range of glycoproteins (HSV encodes 12 different glycoproteins)
to enter cells. This association of various glycoproteins in attachment and
entry process has proven to pose several challenges in retargeting of HSV as
many of these glycoproteins contribute to viral tropism. Therefore,
understanding the interaction and contribution of HSV gD, gC, gB, and gH/gL
(essential glycoproteins for entry) in attachment and entry is crucial in
retargeting HSV. HSV gB and gC encounter and bind to heparin sulfate
proteoglycan (HSPG) present in many cells of the body. This interaction initiates
binding to specific entry receptors for example, binding of gD with the TNF
receptor superfamily member HVEM or nectin-1, etc.

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strategies have been employed for HSV vector retargeting, such as a) the use of
pseudotyped virus (e.g. G-glycoprotein from vesicular stomatitis virus (VSV-G)
pseudotyped various viruses) replacing one or more HSV glycoproteins with those
of another virus which has a different natural tropism. This has illustrated
that HSV-1 entry mechanism can be manipulated, b) the use of adapter molecules
that are capable of binding to both HSV gD and the desired target receptor, though
require the virus to be mixed with adapter prior to infection in order to gain
entry via target receptor, c) Finally, the incorporation of peptide ligands and
single-chain antibodies (scFvs) into HSV gD, gC or gH with the combination of
specific deletions and mutations have enabled complete retargeting. Studies
relating to this have been performed in order to restrict oncolytic HSV (oHSV)
infection to only specific tumor cell types by replacing canonical
receptor-binding sequences, as a result this retargeting strategy has been
proven most efficacious. Earlier findings regarding development of oHSV vectors
(Shibata, 2016) have highlighted this, whereby a targeting scFv was exclusively
constructed and introduced into gD with the inclusion of mutations have enabled
retargeting to EpCAM-bearing or EGFR-bearing tumor cells. In this study, it was
determined that the EGFR-retargeted virus was unable to infect the colon cancer
tumors and hence effective in treatment, while the EpCAM-retargeted oHSV will
not infect and kill glioma tumors.

 Further studies have been conducted to
determine the plasticity of HSV-1 gD to tolerate insertion or deletion
mutations with the aim to develop an oncolytic HSV-1 vector (Fan,2017). In
these studies, the cell surface expression was examined to establish how such mutations
in gD can alter the expression. The gD insertion mutations were found to alter
receptor usage in cell-cell fusion. Moreover, it was also examined that soluble
scFv-gD bound to neuroblastoma meanwhile an HSV-1 recombinant comprising the
same soluble scFv-gD was unable to infect neuroblastoma cells expressing GD2.
Findings from this study attempted to retarget gD to use GD2 as a receptor,
however concluded that insertion of longer protein sequences at different sites
of N-terminus of gD does not interfere fusion with nectin-1.


further studies are required, these studies have illustrated the versatility of
retargeted HSV in treatment of various cancers.

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