8 Gene-transfer Tool: Herpes Simplex Virus Vectors

Abstract

The clinical application of gene therapy to treatment of human disease depends on the development of effective gene-transfer vectors. Although considerable technical progress has been made in recent years, a number of obstacles remain. These can be considered in the following categories: (1) toxicity of the vector, including direct cytopathic effects and the potential inflammatory or immune responses; (2) transgene expression, including the efficiency of cellular transduction, the level and duration of expression, and the potential to regulate expression; (3) transgene capacity of the vector; and (4) targeting of the transgene expression to specific cell populations. Some vector systems may overcome many of these obstacles for particular tissues or applications, and attention to the unique biological properties of individual vectors has begun to provide opportunities to meet the challenges of effective gene delivery.

The human herpesviruses represent excellent candidate vectors for several types of applications. As a class, they are large DNA viruses with the potential to accommodate large or multiple transgene cassettes, and they have evolved to persist in a lifelong nonintegrated latent state without causing disease in the immune-competent host. Among the herpesviruses, herpes simplex virus type 1 (HSV-1) is an attractive vehicle especially for gene transfer to the nervous system because its natural history of infection in humans includes lifelong persistence in neurons. Latency is characterized by the absence of viral protein expression, and there is no evidence of neurodegeneration caused by latent genomes. The virus contains a unique, neuron-specific promoter system that remains active during latency...