Herpesvirus Vectors in Gene Therapy

Herpes simplex virus type 1 (HSV-1) is a common human virus, best known as the causative agent of recurrent labial herpes (cold sores) [1]. The unique properties of HSV-1 have increasingly been exploited in vector design, particularly for therapy of the central nervous system diseases. HSV has natural properties useful for a therapy vector: the latent, lifelong infections in the nervous system with long-term gene expression, the episomal non-integrating DNA genome and the numerous dispensable genes allowing cloning of large transgenes and their regulatory sequences [2]. Numerous clinical phase I-III studies using HSV vectors are in progress on therapy of gliomas and other malignancies and of other, mainly neurological, disorders, including pain [3, 4]. The HSV vectors can be genomic, nonreplicating or replicative vectors, or HSV amplicons. HSV amplicons are vectors harboring only minimal amount of virally derived sequences, suitable for delivery of up to 150 kbp of foreign DNA [5]. The use of HSV amplicon vectors has further been improved by the development of HSV-adeno-associated virus (AAV) hybrid vectors, aiming at long-term transgene expression. The wild type HSV, and also the HSV vectors, can evoke both innate and adaptive immune responses in the host organism [6]. The host responses can limit the vector persistence and duration of the transgene expression, but may occasionally also be advantageous in therapy of certain diseases. The current special issue introduces to the reader the different types and uses of HSV vectors, as well as the host responses which may affect the performance of these vectors. In this issue, Tsitoura and Epstein provide an expert overview of the HSV amplicon vectors and the host responses. They discuss the challenges in overcoming the amplicon silencing in the host, as well as the roles of certain HSV genes in counteracting the host responses. The review by de Oliveira and Fraefel introduces the HSV/AAV hybrid vectors, and illustrates also the biology of AAV and AAV vectors. The relevant helper viruses and HSV vectors are discussed, and new hybrid virus vectors are presented, such as HSV/Epstein-Barr virus and HSV/retrovirus hybrids. The overview by Cassady and Parker elucidates the use of HSV in tumor killing. They present the conditionally replicating HSV vectors for brain tumor therapy. In their paper, various approaches are illustrated for enhancement of tumor killing by HSV, such as combination of HSV virotherapy with other therapeutic modalities, or the tumor-specific targeting of HSV vectors. The authors …