HSVtk

HSVtk refers to the Herpes simplex virus type 1 thymidine kinase gene, encoding an enzyme that phosphorylates certain nucleoside analogs. In gene therapy, HSVtk is used as a suicide gene: cells expressing the enzyme convert administered prodrugs, such as ganciclovir, into toxic nucleotide triphosphates that terminate DNA synthesis and trigger cell death. The toxic effect can extend to neighboring cells through the bystander effect, facilitated by gap junctions and extracellular diffusion of phosphorylated metabolites.

Delivery is accomplished by introducing the HSVtk gene into target cells using viral vectors (retroviral, adenoviral, adeno-associated virus, lentiviral) or non-viral methods. The approach aims to selectively kill diseased cells while sparing surrounding tissue. HSVtk has also been developed as a reporter gene for molecular imaging: radiolabeled substrates such as 18F-FHBG enable positron emission tomography to monitor transgene expression in vivo.

In clinical practice, HSVtk–mediated suicide gene therapy has been tested primarily in cancer trials, including glioblastoma and other solid tumors, often in combination with conventional therapies. Results have been mixed, with challenges including limited vector delivery efficiency, immune responses to the viral gene, and variable expression of the enzyme. The bystander effect can aid efficacy but also raises concerns about damage to normal tissue.

Safety considerations include potential immunogenicity of the viral enzyme, insertional mutagenesis with integrating vectors, and off-target prodrug activation. To date, HSVtk remains a valuable research tool and a platform for imaging and targeted therapy, but broad clinical adoption has been limited and ongoing advances focus on better delivery, regulation of expression, and reducing toxicity.