5-1.4.3. Herpes virus vectors
• The herpes viruses are linear ds-DNA viruses of approximately 150 kb size e.g. EBV (Epstein–Barr virus ) and the HSVs ( Hepatitis B virus, e.g. HSV-I, varicella zoster).
• Most HSVs are transmitted without symptoms (varicella zoster virus is exceptional) and cause prolonged infections.
• With the help of two viral glycoproteins, gB and gD, the virus binds to cells through an interaction with heparan sulphate moieties on the cell surface.
• Unlike EBV as a replicon vector (contains both cis and trans acting genetic elements required for replication), HSV-I have been developed as a transduction vector for purpose of gene transferand can efficiently transduce a wide range of cell types.
• HSV virus is remarkably neurotropic and thus HSV vectors are particularly suitable for gene therapy in the nervous system. HSV can also be transmitted across neuronal synapses during lytic infections which can be used to trace axon pathways.
• Generation of recombinants in transfected cells takes place by homologous recombination. These viral vectors may be replication competent or helper dependent.
• The plasmid based amplicon vectors carrying only the cis -acting elements required for replication and packaging can be constructed. These vectors require packaging systems to provide the missing functions in trans .
Role in gene therapy
Most promised use of HSV vectors involves gene transfer to neural cells where it can cause a latent infection (e.g. spinal cord, brain, and peripheral nervous system).
Advantages
- Infects a wide range of cell types
- Insert size up to 50 kb due to large viral genome size
- Natural tropism to neuronal cells
- Stable viral particles allow generation of high virus titres (1012pfu/ml)
Disadvantages
- No viral integration into host genome and transient transgene expression
- High level of pre-existing immunity
- Cytotoxicity effects
- Risk of recombination with latently HSV-infected cells