HSV Recombinant Vectors for Gene Therapy~!2009-12-17~!2010-13-31~!2010-06-17~!

Abstract

Abstract:The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges.Keywords: HSV, viral vectors, oncolytic vectors, gene therapy, neurodegenerative disorders, cancer, targeting, vaccines. THE HERPES SIMPLEX VIRUS LIFE CYCLEHerpes simplex virus (HSV) is an enveloped, doublestranded (ds) DNA virus [1]. The mature virion consists of different components: an external envelope containing about 13 glycoproteins involved in different functions, among which the first steps of binding and entry into the host cell; an amorphous layer known as the tegument, containing some 20 different proteins with structural and regulatory roles; and an icosadeltahedral capsid containing a toroidal dsDNA. The HSV-1 genome consists of 152 kb of linear, dsDNA arranged as long and short unique segments (UL and US) flanked by inverted repeated sequences (TRL/IRL and IRS/TRS, respectively) (Fig. 1). The repeated regions of the viral genome contain two immediate-early (IE) genes [infected cell protein (ICP) 4 and ICP0], a late (L) gene (ICP34.5) and the latency associated transcripts (LAT) that are each present in two copies. Thus, the repeated region located between the long and short segments of the genome (the joint repeat region) contains a single copy of each gene. HSV genome encodes approximately 90 genes that can be classified as essential or nonessential based on their requirement for virus replication in tissue culture. Essential genes are required for virus growth such that viral mutants lacking these genes can only establish a lytic infection if the missing genes are supplied in trans by an engineered c...

Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

“…Yellow boxes represent BAC and reporter cassettes unrelated to the viral life cycle. Black arrows represent nonessential viral genes, while red arrows represent essential viral genes (46). The blue and green boxes represent the long and short terminal repeats, respectively.…”