Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 53

is regulated mainly at the transcriptional level, begins with the
expression of the immediate-early (IE) genes. The resulting IE
(or alpha) gene products are mostly regulatory proteins responsi-
ble for controlling viral gene expression during subsequent, early
(E or beta) and late (L or gamma) phases of the replication cycle
and for inducing shutoff of cellular protein synthesis. The IE
proteins are known as ICP0, ICP4, ICP22, ICP27, and ICP47.
With the exception of ICP47, whose function is to inhibit antigen
presentation by the MHC class I molecules, the other IE proteins
play different regulatory roles during the life cycle of the virus.
Transcription of IE genes occurs in the absence of de novo viral
protein synthesis and is highly stimulated by a virion tegument
protein known as VP16, which is a powerful transcription factor.
The early (E) gene products that are synthesized next comprise (1)
several enzymes that act to increase the pool of deoxynucleotides
of the infected cells such as a thymidine kinase (TK) and a ribo-
nucleotide reductase (RR) and (2) 7 replication proteins involved
in viral DNA synthesis including DNA polymerase and a primase/
helicase complex. The last set of genes expressed are the late (L)
genes, which encode the structural proteins involved in the assem-
bly of the capsid, the tegument, and the envelope of the virus par-
ticles, including some proteins, such as VP16 and vhs, which play
important roles very early during the next infectious cycle.
Lytic viral replication results in the impairment of host macro-
molecular synthesis, the production and release of newly assembled
progeny particles, and the ultimate death of the host cell [ 1 ].
Interestingly, about 50 % of the proteins expressed during the lytic
cycle are not essential in cell culture and can be deleted without
signifi cantly perturbing virus production in vitro. These proteins
are thought however to play important roles in vivo such as control
of neurovirulence or escape from immunity or apoptosis [ 3 ].
During latency in the sensory ganglia, the viral genome remains as
a circular chromatinized episome within the neuron nucleus and
undergoes dramatic structural changes resulting in an almost com-
plete silencing of transcription. Only the LAT locus is actively tran-
scribed during latency, resulting in the synthesis of nonmessenger
RNA molecules whose function is not yet completely elucidated,
though some evidences suggest that it can inhibit virus-induced
neuron apoptosis [ 5 ]. In addition, the LAT RNA encodes at least
8 miRNA that act most probably to downregulate expression of
key lytic viral genes and seem to be important in the control of the
switch between lytic and latent infection [ 4 ].

6 HSV-1-Based Vectors

HSV-1 presents several outstanding adaptations to the nerve system,
and each of them can be rationally exploited in the design of gene
therapy vectors with regard to neurological applications [ 6 , 7 ].