The Virtues and Vices of Harnessing HSV Vectors for CNS Autoimmunity Modulation

Abstract

HSV type 1 (HSV‐1) is a common human path‐ ogen, known as the causative agent of recurrent labial herpes (cold sores). HSV is one of the most extensively studied viruses. The broad knowledge on HSV pathogenesis and viral gene functions have enabled the construction of safe HSV vectors for gene therapy purposes. HSV‐1 has natural properties, which are favor‐ able for therapy vectors: the life‐long latent form of infection in the nervous system, which could be exploited for long‐term transgene expression, and the episomal DNA genome, which does not integrate into the host genome. Due to numerous dispensable genes, clon‐ ing of large or multiple transgenes into HSV can be accomplished. The drug susceptibility gene, HSV thymidine kinase, is present in the genome of wild‐type HSV and in most HSV vectors. Moreover, HSV‐1 is a neurotropic virus, naturally seeking its way to the nervous system, making HSV‐1 a promising gene therapy vector candidate for CNS diseases [1,2]. Clinical trials have so far mainly explored HSV‐1 vectors as oncolytic viruses for therapy of brain tumors or other cancers, for example, melanoma [1,3,4]. Similar HSV vectors have potential for gene therapy of neurological disorders, particularly pain [1,2] and CNS autoimmune disease. In this article, we discuss gene therapy of experimen‐ tal autoimmune encephalomyelitis (EAE), the premier animal model for multiple sclerosis (MS). MS and EAE are inflammatory diseases of the CNS, where autoreactive T cells attack the myelin sheath surrounding the nerve axons. Inflammation, axonal loss and demyelination are hallmarks of the diseases. There is still a lack of curative pharmacological therapy for MS, and the current semiselective immuno‐ modulative drugs may predispose some patients