Editorial [Hot Topic: Herpes Simplex Virus Type 1-Based Amplicons Vectors (Guest Editor: Alberto L. Epstein)]

The study by Richard R. Spaete and Niza Frenkel [Spaete et al., 1982] that can be considered as the birth of the concept of herpes simplex virus type 1 (HSV-1) amplicons was published almost 25 years ago, giving us a good opportunity to celebrate this event. That paper was actually the climax of a series of very elegant and clever fundamental studies aimed to identify and characterize the origins of virus DNA replication, the packaging signals, and the packaging mechanisms of the HSV-1 genome, as developed in the introductory review to this special issue of Current Gene Therapy, written by Niza Frenkel. At the same time, that paper represented the beginning of one of the most interesting, useful, and powerful systems of viral vectors for gene transfer and gene therapy. After the initial demonstration, by Kwong and Frenkel in 1985, that amplicons could be used to efficiently deliver foreign DNA into cultured cells [Kwong et al., 1985], and the publication, by Geller and Breakefield in 1987, of the first study showing that these vectors could be used to express beta-galactosidase in rat cultured peripheral neurons (Geller and Breakefield, 1988), more than 200 papers have reported advances in amplicon technology or applications to gene transfer using these vectors. A first group of studies, too large to be referred to in detail in the scope of this short overview, aimed to improve the production of amplicon vectors both in terms of amount of infectious particles and of purity, in regard to the contamination with helper virus particles [Fraefel et al., 1996, Saeki et al., 2001, Zaupa et al., 2003], as exemplified in particular by the review of K. Kasai and Y. Saeki. Simultaneously, other studies focused on the possibility of expanding the host range of amplicon application by introducing viral or cellular genetic elements allowing vegetative replication or maintenance of the amplicon genome in proliferating cells [Wang et al.,1996], or by improving the stability of the transduced transgene via its integration into targeted loci of the cellular genome, using the adenovirus-associated vector system (Fraefel et al., 1997, Johnston, et al., 1997], as illustrated by the review of D. Glauser et al., Also in the same technological chapter, we should refer to the outstanding work developed by A. Chiocca, Y. Saeki, R. Wade-Martins and colleagues [Wade-Martins et al., 2001, Wade- Martins et al., 2003] to demonstrate that it was possible to use amplicons to transfer entire genomic loci, as developed in the review by Hibbit and Wade-Martins, opening the way to study how the use of long native regulatory sequences could confer physiological regulation of expression to the transgenic sequences. About half of the papers reporting applications of amplicon vectors to particular experimental systems, relate to the nervous system. Many studies have confirmed the strength of these vectors to protect neurons against a variety of natural or experimental injuries via expression of neurotrophins, antiapoptotic or antioxidant molecules, heat-shock proteins or proteins affecting neuronal metabolism. Other studies have shown that amplicons offer a way to study and modify behavioral traits, like anxiety, sexual behavior, learning, and memory, while still others have focused on the possibility of using amplicons to study and treat brain cancers or neurodegenerative diseases, in particular Parkinson disease. It is impossible to quote all these studies in this short introduction, but the reviews of Tyler et al., Shah and Breakefield, and Jerusalinsky and Epstein are here to illustrate and summarize the particular interest of amplicons in neurobiology and neurology. Although to a lesser extent, other works have used amplicons as gene delivery tools to other cells or tissues, including hepatocytes, dendritic cells, skeletal and cardiac muscle cells, etc. The review by Y. Wang illustrates more particularly the relevance of amplicons as tools for introducing genes into muscle cells. Some studies are currently exploring the ability of amplicons to behave as heterologous vector vaccines [Hocknell et al. 2002] and, in this regard, the ability of amplicons to simultaneously express many different antigens, immunomodulators, or even the whole set of structural viral proteins that could generate empty virus-like particles (VLPs) [Savard et al., 1997, Sena-Esteves et al., 1999] constitutes another outstanding illustration of the significance of these vectors as gene transfer tools. The reviews by Santos et al., and by Tsitoura et al., exemplify these aspects of the potentiality of amplicons. Finally, it is clear that the amplicon concept can be extended to other members of the herpesviridae. This is currently being done by a small number of teams and is illustrated in this issue by the review on HHV-6 and HHV-7 amplicons by Borenstein and Frenkel. The aim of this issue of Current Gene Therapy was to present a picture of the current state-of-the-art technology of amplicon vectors and to illustrate some of the most interesting applications that are currently being developed using these outstanding tools. It is clear that by adopting this point of view, and taking into account the limited size of this journal, it was not possible to invite other researchers for additional contributions other reviews.....