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HERPES

SIMPLEX
VIRAL
VECTORS
HERPES VIRUS

It belongs to the family Herpesviridae and the sub


family Alphavirinae

Herpes simplex virus consists of a large linear DNA


genome of double stranded DNA, atleat 152 kbp

The virion consists of four components

An electron dense core containing viral DNA

An icosahedral capsid

Designated tegument which surrounds the capsid

an envelope
HSV structure
GENES

The genome of Herpes virus encodes some 100-200


genes.

These genes encode a variety of proteins involved in


forming the capsid, tegument & envelope of the virus
as well as controlling the replication & infectivity of
the virus.

Herpes simplex virus 1 & 2 are the 2 species of the


herpes virus family, which causes infections in
humans.

An infection by Herpes simplex virus is marked by


watery blisters in the skin or mucous membranes of
the mouths and lips.
Genomes of HSV-1 & HSV-2 are complex and
contains 2 unique regions called the long unique
region (UL) and short unique region(US).

There are about 74 known ORFs, of which UL


contains 56 viral genes, where as US contains only
12 genes.

Transcription of HSV genes is catalyzed by RNA


polymerase II of the infected host.
HSV gene expression
Immediate early genes, which encode proteins
that regulate the expression of early and late
viral genes ,are the first to be expressed following
infection.

Early gene expression follows to allow the


synthesis of enzymes involved in DNA replication
& the production of certain envelope
glycoproteins.

Expression of late genes occur late, this group


of genes predominantly encode proteins that
form the virion particle.
HERPES VIRUS AS VECTORS

Herpes viruses are currently as a gene transfer vectors due


to specific advantage over other vectors

Vectors derived from HSV have some unique features.


1. very high transgenic capacity allowing to carry
long sequences of foreign DNA.
2. Genetic complexity of the virus genome, allowing
to generate many different types of attenuated vectors
possessing oncolytic activity.
3. They have the ability to invade and establish
lifelong non-toxic latent infections in neurons from sensory
ganglia from where transgenes can be strongly expressed.
Latent infection in post-mitotic neurons has generated
substantial interest in using it to deliver therapeutic genes to
the nervous system.
4. These vectors have a wide host range & cell
tropism.

Eg: Oncolytic HSV vectors are promising therapeutic agents


for cancer. Such HSV based vectors have been tested in
glioma, melanoma & ovarian cancer patients.

There are many different disorders that affect the central and
peripheral nervous systems, including tumours, metabolic &
immunological defects & neurodegenerative syndromes such
as alzheimer & parkinson diseases.

Herpes viruses are neurotrophic viruses, which on suitable


modification can be effectively used for gene therapy in central
nervous system disorders
Herpes virus has a natural affinity for non-dividing cells
and hence it is suitable for transfection of neurons.

The virus fuses to the membrane of a neuron & is


transported to the nucleus.

About 30 Kb of the HSV genome can be replaced by cloned


DNA without significant effects on replication, packaging or
infectivity.

Larger size of the virus makes genetic manipulation a


difficult task, which is overcome by a scaled down version
of HSV genome consisting of the HSV origin of replication
& packaging signal has been incorporated into an E.coli
plasmid that can, in addition, carry upto 8Kb of cloned DNA
pHSVlac Amplicon Vector
Lysosomal Disorder

Berges B.K. and colleagues have used HSV1716 attenuated


vector, an ICP34.5 null mutant, to treat Mucopolysaccharidosis
(MPS) VII.

MPS VII is caused by a gene deficiency in the lysosomal


enzyme glucoronidase (GUSB) with consequent accumulation
of glycosaminoglycans (GAGs) affecting a number of organ
systems.

The investigators have demonstrated the capacity of HSV1716


virus expressing GUSB driven by the latency-associated
transcript promoter (HSV-1716-LAT-GUSB virus) to correct
the lysosomal storage in the adult MPS VII mouse model
following intracranial injection.
The authors have shown that this neuro attenuated vector
was able to establish latency and to express GUSB at a
distance from the site of injection

And the correction of the lysosomal storage was


demonstrated in several brain regions.

This result was the consequence of the ability of neuro


attenuated vectors to traverse at least one neuronal synapse
and achieve gene expression in a secondary neuron

Followed by the secretory properties of GUSB that can


cross-correct a larger brain area.
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