Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 54

HSV-1 contains genes that control neuroinvasiveness and neuro-
virulence; the virus can move both in the retrograde and antero-
grade directions and disseminates transsynaptically from neuron to
neuron [ 8 ]. The ability to be retrogradely transported can be use-
ful in studying the physiopathology of motor and sensory neurons,
because vectors inoculated into muscle or into the skin, can induce
transgene expression in the cell bodies of ventral-horn or sensory-
ganglion neurons [ 9 ]. The virus envelope contains glycoproteins
that mediate entry to neurons due to the recognition of specifi c
receptors [ 10 ]. As above quoted, in many sensory neurons HSV-1
can establish a latent infection, a situation in which the viral genome
persists as a stable chromatinized episomal element and in which all
lytic genes are silenced [ 11 , 12 ], and this feature could also be
exploited in the design of effi cient vectors.
Many studies indicate that most of these neurotropic features
are retained in defective and attenuated HSV-1 vectors, including
the abilities to be effi ciently transported along axons in both direc-
tions, and to establish latent infections with prolonged gene
expression, both in sensitive and in motor neurons. The interest
and uniqueness of HSV-1-based vectors stem from three outstand-
ing properties of HSV-1, not shared with other viral systems.
The fi rst of these properties is the very large capacity of the virus
particle, which allows packaging and effi cient delivering of up to
150 kbp of DNA to the nuclear environment of mammalian cells.
This DNA will remain as a nuclear episome from where the trans-
genes will be expressed. The nonintegration of the vector genome
into the host chromosomes considerably decreases the risk of
insertional mutagenesis. The second property is the vast complex-
ity of the virus genome, which contains some 40 genes that are not
essential for virus replication in cultured cells and can therefore be
deleted without disturbing virus production, yet they are required
for expression of a fully virulent phenotype in vivo. This property
allows the rational design of different types of attenuated vectors.
The third property is the above-mentioned remarkable set of
adaptations of HSV-1 to the nervous system, including the ability
to trans-synaptically spread from neuron to neuron in both direc-
tions, and the capacity to establish latent infections in neurons, a
nontoxic condition that allows strong and stable transgene expres-
sion under the control of the latency-associated promoter (LAP)
or other appropriate promoters.
Three different types of vectors can be derived from HSV-1,
which attempt to exploit one or more of the above-mentioned
properties: attenuated recombinant vectors, defective recombinant
vectors, and amplicon vectors. Defective recombinant vectors
(Fig. 4a ) are disabled, replication incompetent and nonpathogenic
HSV-1 mutants lacking one or more essential genes. These vectors
retain many advantageous features of wild type HSV-1, particularly
the ability to express transgenes after having established latent
infections in central and peripheral neurons [ 13 , 14 ]. Attenuated