Designing Herpes Viruses as Oncolytics

Abstract

Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because herpes simplex virus (HSV) is a natural human pathogen that can cause serious disease, it is incumbent that it be genetically-engineered or significantly attenuated for safety. Here we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are non-essential for growth in tissue culture cells but are important for growth in post-mitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be 'armed' with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate anti-tumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity.

Figure 1

Schematic map of herpes simplex virus (HSV) genome illustrating the position of genes (IE, E, L) deleted or mutated in oHSVs. The genome consists of unique long (L) and short (S) sequences bracketed by terminal (TR) and internal (IR) inverted repeat sequences and separated by the joint region. The number of a sequence repeats is variable. Arrows indicate direction of transcription.