A Thymidine Kinase-Negative HSV-1 Strain Establishes a Persistent Infection in SCID Mice That Features Uncontrolled Peripheral Replication but Only Marginal Nervous System Involvement

• Published in: Virology (New York, N.Y.) Vol. 199; no. 2; pp. 484 - 490
• Main Authors: Valyi-Nagy, Tibor, Gesser, Richard M., Raengsakulrach, Boonyos, Deshmane, Satish L., Randazzo, Bruce P., Dillner, Allan J., Fraser, Nigel W.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.03.1994; Elsevier
• Subjects: AIDS/HIV; Animals; Biological and medical sciences; Disease Models, Animal; Experimental viral diseases and models; Herpes Simplex - microbiology; herpes simplex virus; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - pathogenicity; Herpesvirus 1, Human - physiology; Infectious diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, SCID; Neurons - microbiology; Thymidine Kinase - physiology; Viral diseases; Virus Replication - physiology; Tropism; Animal model; Thymidine kinase; Enzyme; Pathogenesis; Herpesviridae; Transferases; Alphaherpesvirinae; Rodentia; Nervous system; Immune deficiency; Virus; Vertebrata; Experimental disease; Mammalia; Herpesvirus hominis 1; Mouse; Persistent infection; Replication
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1006/viro.1994.1150

A detailed knowledge of the pathogenesis of infections caused by thymidine-kinase (TK)-deficient herpes simplex virus type 1 (HSV-1) strains is important because such mutants can arise during treatment of HSV infections with acyclovir—especially in immunocompromised patients—and also because TK-negative mutants may become useful for the therapy of intracranial tumors. In this work, we studied the pathogenesis of a genetically engineered TK-negative HSV-1 strain dlsptk, in SCID mice (mice with severe combined immunodeficiency) after corneal infection. We found that dlsptk established a persistent infection that kills SCID mice within 80.2 ± 21.3 days. The cause of death seemed to be r elated to uncontrolled viral replication in the superficial and deep facial tissues of the animals. Viremia probably did not occur, as judged by the inability to detect infectious virus and vital gene expression in various internal organs. However, the virus did reach the nervous system, most probably by axonal transport from the primary site of the infection. Virus-specific DNA reached low but detectable levels in the trigeminal ganglia and the brainstems by 7 days p.i. and remained at low levels for up to 50 days p.i. as determined by spot blot analysis. By in situ hybridization and immunostaining we determined that, in some of the neurons of the trigeminal ganglia infected by the virus, vital latency was established. However, our results suggested that in other infected neurons viral replication occurred and virus spread to surrounding nonneuronal cells and to the central nervous system. This work provides a new model in which the pathogenesis of infections caused by TK-deficient HSV strains in immunocompromised hosts can be effectively studied and which may also help to identify the potential side effects of the therapy of intracranial tumors with TK-negative HSV strains.