Each class of viral vectors displays a set of features that makes them unique and suitable for particular applications. The uniqueness of herpes simplex virus (HSV-1)-based vectors stems from three outstanding properties of HSV-1, not shared with any other viral system. The first of these properties is the very large capacity of the virus particle, which allows to package and efficiently deliver up to 150 kbp of DNA to the nuclear environment of mammalian cells. This DNA will not integrate into host chromosomes and the genes carried by these molecules will be expressed from the episomic genome. The second property is the astonishing complexity of the virus genome, which contains more than 80 genes among which around half are not essential for virus replication and can therefore be deleted without disturbing virus production in culture conditions, yet they are required for expression of a fully virulent phenotype in vivo. The third property is the remarkable set of adaptations of HSV-1 to the nerve system, which includes phenotypes like (i) the ability to trans-synaptically spread from neuron to neuron in both anterograde and retrograde directions, (ii) the capacity to establish latent infections in neurons, a nontoxic situation characterized by the total repression of expression of virus lytic genes and (iii) the presence of neurospecific regulatory sequences conferring strong and long-term expression in neurons during latency.
The three different types of vectors that can be derived from HSV-1 attempt to exploit one or more of these properties. Attenuated recombinant vectors are replication-competent HSV-1 carrying different kinds of attenuating mutations that will restrict spread and lytic replication of the virus only to actively dividing cells, like cancer cells, but without causing local or systemic toxicity as they fail to replicate within normal tissues. These vectors, which are used mainly, although not only, as oncolytic agents, are described in the accompanying article by Manservigi and co-workers. Defective recombinant vectors 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 stably express transgenes after having established latent infections in central and peripheral neurons, but cannot replicate in, and therefore cannot disseminate out of, the inoculated cells. As described in detail in the article by Marconi and co-workers in this supplement, these vectors are produced on specially constructed trans-complementing cell lines expressing the genes that lack in the vector genome. Lastly, amplicon vectors are defective, helper-dependent vectors that take advantage essentially of the large transgenic capacity of the virus particle. Actually, there is no other mammalian vector available that could equal the ability of amplicons to deliver 150 kbp of foreign DNA with no simultaneous delivering of viral genes, as developed in the article by AL Epstein in this issue of Gene Therapy.
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