Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 65

reduces the possibility of toxicity derived from the systemic admin-
istration of the molecule.
Other groups have tested oncolytic HSV strains encoding
different prodrug-activating systems, other than the endogenous
TK activity of the virus. Both the 5-fl uorocytosine (5-FC) pro-
drug/yeast cytosine deaminase (CD) gene system [ 96 ], alone or in
combination with the TK/ganciclovir system, and the cytochrome
P-450/cyclophosphamide (CPA) system [ 97 , 98 ], were shown to
induce benefi cial effects [ 99 ]. Overall, the results so far obtained
demonstrate that incorporating suicide and/or cytokine transgenes
in the viral genome can increase antitumor effi cacy, especially if
used in combination with preexisting anticancer treatments such as
chemotherapy or radiotherapy [ 100 ].
In addition, it appears to be possible to target cancer cells at the
level of virus entry since the entry apparatus of HSV-1 is consider-
ably well known. The host range of HSV-1 can be altered by genetic
manipulation of the receptor-binding virus glycoproteins by insert-
ing a binding domain for target receptors, which should be selec-
tively expressed or overexpressed in tumor cells, but absent or
expressed at low levels in normal cells. The major work has been
done with glycoprotein D (gD) [ 101 ] a protein that, following the
initial attachment, interacts with at least two distinct protein recep-
tors, herpesvirus entry mediator (HVEM) and nectin-1 [ 10 , 102 ].
Zhou et al. have targeted the entry of the virus into malignant gli-
oma cells through IL13R 2 receptor, which has been reported to

be expressed in malignant gliomas. They report that an IL-13-gD
chimeric virus can use IL13R

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2 for entry into cells carrying only
that receptor [ 103 , 104 ]. This was the fi rst evidence that HSV-1
recombinant viruses can be effectively engineered to enter cells via
a variety of unrelated nonviral receptors that are anchored to the
cell surface [ 103 , 104 ]. Chimeric forms of gD carrying heterolo-
gous ligands to the receptor of choice have been showed to redirect
the virus to the ligands' receptors [ 16 , 105 ]. In this context, an
oncolytic HSV-1 was recently engineered to express a form of gD
carrying a single-chain antibody to selectively target HER2-
expressing tumor cells, while having lost the ability to enter cells
through the natural gD receptors, by deleting the peptides in gD
that interact with HVEM and nectin 1 [ 106 ].
Alternatively, some studies have addressed the possibility of tar-
geting viral expression/replication to specifi c types of cells through
the use of cancer-specifi c promoters to target transcription [ 107 ].
Although some of these studies have produced quite encouraging
results, it is equally clear that further investigations are required to
identify both the promoters that will allow the best possible targeting
to a particular cancer tissue, and the virus genes whose expression
should be targeted in order to obtain those goals.
The key concept of targeting virus entry and/or multiplication
to specifi c tumor cells is to improve effi cacy, with minimum or no

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