HSV-1-Derived Recombinant and Amplicon Vectors for Gene Transfer and Gene Therapy

Abstract

Herpes simplex virus type 1 (HSV-1) is a 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. Although in most cell types infection with HSV-1 will induce toxic effects ending in the death of the infected cells, the very deep knowledge we possess on the genetics and molecular biology of HSV-1 has permitted the deletion of most toxic genes and the development of non-pathogenic HSV-1-based vectors for gene transfer. Several unique features of HSV-1 make vectors derived from this virus very appealing for preventive or therapeutic gene transfer. These include (i) the very high transgenic capacity of the virus particle, authorizing to convey very large pieces of foreign DNA to the nucleus of mammalian cells, (ii) the genetic complexity of the virus genome, allowing to generate many different types of attenuated vectors possessing oncolytic activity, and (iii) the ability of HSV-1 vectors to invade and establish lifelong non-toxic latent infections in neurons from sensory ganglia and probably in other neurons as well, from where transgenes can be strongly and long-term expressed. 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. Each of these different vectors attempts to exploit one or more of the above-mentioned features of HSV-1. In this review we will update the current know-how concerning design, construction, and recent applications, as well as the potential and current limitations of the three different classes of HSV-1-based vectors.

Viral vector-induced expression of bone morphogenetic protein 2 produces inhibition of tumor growth and bone differentiation of stem cells

“…10,11,22 HSV vectors are particularly attractive. They are safe and 490% of humans have antibodies directed against HSV, indicating wide exposure, but few have clinical sequelae.…”

“…One particularly promising family of virus-based vectors used in cancer therapy is derived from the herpes simplex virus (HSV) type-1. 10,11 This virus, which in its wild-type form produces cold sores, has been genetically engineered to be even safer and to efficiently transduce a broad spectrum of human cancers. 10,11 In this study, we employ replication-incompetent HSV amplicon vectors.…”

“…10,11 This virus, which in its wild-type form produces cold sores, has been genetically engineered to be even safer and to efficiently transduce a broad spectrum of human cancers. 10,11 In this study, we employ replication-incompetent HSV amplicon vectors. These vectors harbor no viral genes, only the non-protein encoding packaging sequence (pac) and HSV origin of replication to facilitate the propagation of viral particles.…”

Use of herpes simplex virus type 1-based amplicon vector for delivery of small interfering RNA

“…[11][12][13] These vectors possess three outstanding properties. First, the large capacity of the virus particle allows to package and efficiently deliver up to 150 kbp of DNA.…”

“…11,15 HSV-1 amplicons are bacterial plasmids containing two non-coding, genetic elements from HSV-1, an origin of DNA replication and a packaging/cleavage signal, which allow their replication and packaging as a 150 kb concatamer into HSV-1 particles. HSV-1 helper functions can be provided by replication-competentpackaging-defective HSV-1 genome, cloned as a bacterial artificial chromosome, to yield the amplicon particle (vector).…”