HSV as a Vector in Vaccine Development and Gene Therapy

Abstract

The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), major human pathogen whose lifestyle is based on a long-term dual interaction with the infected host characterized by the existence of lytic and latent infections, has allowed the development of potential vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous system, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases and targeted infection of specific tissues or organs. Three different classes of vectors can be derived from HSV-1: replication-competent attenuated vectors, replication-incompetent recombinant vectors and defective helper-dependent vectors known as amplicons. This chapter highlights the current knowledge concerning design, construction and recent applications, as well as the potential and current limitations of the three different classes of HSV-1-based vectors.

Medical application of herpes simplex virus

“…These advantages include: (i) the broad host range that allows HSV to infect and replicate almost all cell lines; (ii) infectivity both in replicating and non-replicating cells such as neuronal cells; (iii) the potential for incorporating a large size of foreign DNA; (iv) their control by anti-herpetic agents such as aciclovir (ACV) or ganciclovir (GCV); (v) their ability to exist stably as episomes in neuronal cells, allowing long-lasting foreign gene expression; (vi) the use of mice, guinea pigs and monkeys as models due to the similarity in viral pathogenicity in these animals to that in humans; (vii) the determination of complete open reading frames and identification of disease-related viral genes [8,9]. While strong immunogenicity and cell toxicity induced by HSV infection are major disadvantages for developing gene delivery vectors using HSV, they are beneficial when developing vaccine vectors or anti-cancer agent by HSV recombination.…”

Viral vectors for gene delivery to the central nervous system

“…Several different types of vectors have been derived from HSV (Marconi et al, 2009; Shen and Post, 2007). Attenuated (‘replication-conditional’) vectors are deficient in expression of viral genes essential for replication in non-dividing, but not dividing cells (e.g.…”

“…Identification of the minimal cis-acting sequences necessary for virus replication, the cleavage/packaging signal and the viral origin, provided another significant advancement in the design of HSV vectors (Spaete and Frenkel, 1982). Amplicon vectors contain only these elements and have a packaging capacity of ~150 kb (Epstein, 2009; Marconi et al, 2009). These vectors have several advantages over attenuated or replication-defective vectors, including lack of viral genes that might cause cytotoxicity and maximal transgene coding capacity.…”

“…Amplicon vectors expressing the anti-apoptotic peptide Bcl-2, neurotrophic factors GDNF and BDNF, and enzymes of the dopamine biosynthesis pathway have shown protection against neuron degeneration in a rat model of Parkinson’s disease (Sun et al, 2005; Sun et al, 2003; Yamada et al, 1999). Also, replication-conditional vectors have been researched extensively for their oncolytic properties and applied in the clinic to treat glioblastoma multiforme and other cancers (Marconi et al, 2009; Markert et al, 2009; Markert et al, 2000; Shen and Post, 2007). …”

Pseudovirions as Vehicles for the Delivery of siRNA

“…The particles are structurally identical to wild-type HSV-1 viral particles, i.e., DNA associated with core proteins, surrounded by an icosohedral nucleocapsid, tegument, and viral envelope. The resulting amplicon vector contains only the linear concatameric form of the plasmid and does not contain any HSV coding sequences (42). Amplicon vectors make use of the inherent, large 150 kb capacity of HSV-1 virions.…”