Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets

Abstract

Alpha-herpesvirus thymidine kinase (TK) genes are virulence-related genes and are nonessential for viral replication; they are often preferred target genes for the construction of gene-deleted attenuated vaccines and genetically engineered vectors for inserting and expressing foreign genes. The enzymes encoded by TK genes are key kinases in the nucleoside salvage pathway and have significant substrate diversity, especially the herpes simplex virus 1 (HSV-1) TK enzyme, which phosphorylates four nucleosides and various nucleoside analogues. Hence, the HSV-1 TK gene is exploited for the treatment of viral infections, as a suicide gene in antitumor therapy, and even for the regulation of stem cell transplantation and treatment of parasitic infection. This review introduces the effects of α-herpesvirus TK genes on viral virulence and infection in the host and classifies and summarizes the current main application domains and potential uses of these genes. In particular, mechanisms of action, clinical limitations, and antiviral and antitumor therapy development strategies are discussed.

Virotheranostics, a double-barreled viral gun pointed toward cancer; ready to shoot?

“…Accordingly, the accumulation of trapped radiotracers can be used as an indicator for in vivo monitoring of viral oncolysis activity over time [36,37]. The main advantage of the HSV-1-TK/nucleoside analog system is its bystander-killing effect by transferring phosphorylated nucleoside analogs from infected cells to surrounding un-transduced tumor cells using the gap junctions or apoptotic vesicles, which enhances the efficacy of virotherapy [36,38]. However, some disadvantages are attributed to this system including (a) limited clinical usage due to the regulatory restrictions associated with the radiolabeled thymidine analogs as investigational drugs, and (b) increased undesirable immune responses related to the non-human origin of exogenous reporter gene [25].…”

Mass Spectrometric Characterization of HSV-1 L-Particles From Human Dendritic Cells and BHK21 Cells and Analysis of Their Functional Role

“…Since HSV-1-infected mDCs predominantly produce L-particles ( Figure 1A ), we exclude the possibility of significant H-particle contaminations in our mDCs preparations. Regarding proteins predicted within the tegument, we detected the UL23 as the most abundant protein, which is responsible for the phosphorylation of thymidine and thus the production of nucleotides for viral DNA synthesis ( Chen et al, 1998 ; Pilger et al, 1999 ; Xie et al, 2019 ). Furthermore, we detected the viral protein ICP32, which is known as larger inner tegument protein, responsible for cytoplasmic secondary envelopment ( Owen et al, 2015 ).…”

Brassicasterol with Dual Anti-Infective Properties against HSV-1 and Mycobacterium tuberculosis, and Cardiovascular Protective Effect: Nonclinical In Vitro and In Silico Assessments

“…Targeting viral and cellular enzymes that perform significant functions during the HSV-1 replication cycle could help the development of effective broad-spectrum antiherpetic drugs. For instance, HSV-1 DNA polymerase was reported to be an essential enzyme required for viral replication [3], while HSV-1 TK is an important enzyme that catalyzes the transfer of the gammaphospho group of ATP to thymidine to generate dTMP in the salvage pathway of pyrimidine synthesis, and hence the dTMP serves as a substrate for DNA polymerase during viral DNA replication [36]. Targeting viral and cellular enzymes that perform significant functions during the HSV-1 replication cycle could help the development of effective broad-spectrum antiherpetic drugs.…”