The Role of Herpes Simplex Virus Type 1 Thymidine Kinase in Pathogenesis

Abstract

SUMMARYA genetically engineered herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) deletion mutant has been constructed and used to investigate the role of this gene in pathogenesis. Inoculation of mice with the HSV TK deletion mutant resulted in the establishment of latent ganglionic infection as demonstrated by superinfection of explanted ganglia with wild-type (wt) virus bat not by routine explant culture suggesting that the virus-encoded TK is not essential for the establishment of latent infection but may be necessary for either reactivation or virus replication following reactivation. In addition, Southern blot hybridization has been used to demonstrate in vivo complementation of this mutant by wt virus in both peripheral and central nervous system tissues of mice during acute infection and to show that such complementation can result in the establishment and reactivation of latent TK-infection.

Latency associated promoter transgene expression in the central nervous system after stereotaxic delivery of replication-defective HSV-1-based vectors

“…Two classes of vectors have been utilised in these studies: (1) replication-defective vectors lacking both the essential glycoprotein H (gH) gene 22 and the nonspecific neurovirulence determinant encoded by the thymidine kinase (tk) gene 23 and (2) a virus mutant severely impaired for immediate early (IE) gene expression designated in1388. 20 gH is essential for virus entry and cell-to-cell spread.…”

Highly Reliable Heterologous System for Evaluating Resistance of Clinical Herpes Simplex Virus Isolates to Nucleoside Analogues

“…The former mechanism is most frequently seen in the clinic (8,16,17,29), probably because TK is not essential for viral replication in most tissues and culture cells (36). However, several reports have demonstrated that TK activity facilitates HSV reactivation from latency in neural ganglia (11,13,44,46).…”

“…The former mechanism is most frequently seen in the clinic (8,16,17,29), probably because TK is not essential for viral replication in most tissues and culture cells (36). However, several reports have demonstrated that TK activity facilitates HSV reactivation from latency in neural ganglia (11,13,44,46).Changes in the TK gene can result in viruses producing no or partial amounts of TK or with an altered substrate specificity (4, 23). Darby et al have proposed a preliminary model for the active center of the HSV type 1 (HSV-1) TK enzyme including three distinct regions: an ATP-binding site (amino acids 51 to 63), a nucleoside-binding site (amino acids 168 to 176), and amino acid 336 (12).…”

Recombinant Viral Vector Vaccines for the Veterinary Use.

“…TK synthesized by alphaherpesviruses appears to facilitate the growth of virus in non-dividing cells [25]. Many recent investigations have demonstrated that TK deficient mutants of herpes simplex virus type 1 (HSV-1) [25], PRV [49,112], BHV-1 [50], equine herpesvirus type 1 (EHV-1) [101], and FHV-1 [131] are remarkably attenuated for their natural hosts or mice and appear to be less readily reactivated from neurons [21]. Kit et al reported the loss of ability of BHV-1 TK deficient mutant to infect the fetus and to cause abortions [51] and the reduction of ability of the mutant to develop latent infections [50].…”