Bovine Herpesvirus Tegument Protein VP22 Enhances Thymidine Kinase/Ganciclovir Suicide Gene Therapy for Neuroblastomas Compared to Herpes Simplex Virus VP22

Abstract

Herpesvirus tegument protein VP22 can enhance the effect of therapeutic proteins in gene therapy, such as thymidine kinase (tk) and p53; however, the mechanism is unclear or controversial. In this study, mammalian expression vectors carrying bovine herpesvirus 1 (BHV-1) VP22 (BVP22) or herpes simplex virus type 1 (HSV-1) VP22 (HVP22) and equine herpesvirus type 4 (EHV-4) tk (Etk) were constructed in order to evaluate and compare the therapeutic potentials of BVP22 and HVP22 to enhance Etk/ganciclovir (Etk/GCV) suicide gene therapy for neuroblastomas by GCV cytotoxicity assays and noninvasive bioluminescent imaging in vitro and in vivo. BVP22 enhanced Etk/GCV cytotoxicity compared to that with HVP22 both in vitro and in vivo. However, assays utilizing a mixture of parental and stably transfected cells indicated that the enhancement was detected only in transfected cells. Thus, the therapeutic potential of BVP22 and HVP22 in Etk/GCV suicide gene therapy in this tumor system is not due to VP22 delivery of Etk into surrounding cells but rather is likely due to an enhanced intracellular effect.

Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide

“…A possible methodology to overcome this problem is to transfer tk to nontransfected cells by fusing it with a protein that is capable of intercellular trafficking. HIV-1 tat and HSV-1 VP22 have been fused to HSV-1 tk, which has enhanced tk suicide gene therapy [21][22][23][24]. In clinical use, the large size of VP22 may become a limitation for gene delivery [25].…”

Protein transduction with bacterial cytosine deaminase fused to the TLM intercellular transport motif induces profound chemosensitivity to 5-fluorocytosine in human hepatoma cells

“…In previous studies this has been addressed by generation of viral vectors encoding fusions of suicide genes with the HIV Tat gene [12], the HSV VP22 gene [13][14][15][16][17], or by direct employment either of a (i) malaria circumsporozoite (CS)-BCDase fusion protein [18] or a (ii) HIV-1 Tat basic domain-YCDase fusion protein [19].…”

Fusion of the HSV-1 tegument protein vp22 to cytosine deaminase confers enhanced bystander effect and increased therapeutic benefit

“…33,34 However, the inherent poor bystander effect of the HSV-TK/ GCV system likely limited the eventual efficacy of this system even with the assistance of vp22-mediated protein translocation. 30,31 Similarly, the bacterial CDvp22 fusion resulted in an enhanced bystander effect in culture, although this system was not evaluated in an in vivo model.…”