Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 63

Development of
experimental settings
(80-86, 93-95, 96-100, 103-106)

Clinical trials
HSV-1 G207 (203-205)
HSV-1 1716 (90,206, 207)

Brain tumours (oncolytic vectors)

Attenuated HSV-1 vectors
in Neurosciences
(reviews 116)

Gene delivery to PNS

Pro-enkephalin (109)
NGF (112)

Fig. 6 Applications of attenuated recombinant vectors. The numbers in square
brackets refer to the list of references. PNS peripheral nervous system

13.1 Oncolytic
Vectors

Because these recombinants retain their capacity to replicate and
kill cells, particularly in actively dividing cells, these replication-
competent HSV-1 viruses are being used as oncolytic therapeutic
agents [ 16 , 78 ]. Construction of oncolytic viruses that selectively
target cancer cells while retaining their ability to replicate, usurp
host replication machinery, and kill these cells, followed by the
release of newly made progeny able to infect other cancer cells and
spread into the tumor, but with no toxicity for the healthy neigh-
boring cells, has become a major area of therapeutic cancer research
[ 15 , 79 ].
Many viral genes that are nonessential in cell culture are
involved in the virulence of HSV-1 in animal models and in the
human beings. Some of these genes have been extensively studied,
in particular the ones encoding (a) thymidine kinase (TK), an
enzyme involved in optimizing nucleic acid metabolism for virus
growth, which is necessary for effi cient replication in neurons [ 80 ,
81 ], (b) ribonucleotide reductase (RR) a protein necessary for the
conversion of rNTPs to dNTPs in neurons, which is required for
effi cient synthesis of progeny viral DNA during virus replication
[ 82 , 83 ], (c) the virion-host shut off (Vhs) function, which causes
rapid destabilization of host RNAs and translational arrest [ 84 , 85 ]
and, most importantly, (d) the ICP34.5 protein, encoded by the
γ

34.5 gene [ 86 ]. The ICP34.5 neurovirulence factor has been
found to be essential for HSV-1 pathogenicity, particularly in the
nervous system. It appears to provide multiple functions to the