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

A detailed knowledge of the pathogenesis of infections caused by thymi dine-kinase (TK)-deficient herpes simplex virus type 1 (HSV-1) strains is important because such mutants can arise during treatment of HSV i nfections 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 ge netically engineered TK-negative HSV-1 strain dlsptk, in SCID mice (mi ce with severe combined immunodeficiency) after corneal infection. We found that dlsptk established a persistent infection that kills SCID m ice within 80.2 +/- 21.3 days. The cause of death seemed to be related to uncontrolled viral replication in the superficial and deep facial tissues of the animals. Viremia probably did not occur, as judged by t he inability to detect infectious virus and viral gene expression in v arious internal organs. However, the virus did reach the nervous syste m, most probably by axonal transport from the primary site of the infe ction. Virus-specific DNA reached low but detectable levels in the tri geminal 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 o f the neurons of the trigeminal ganglia infected by the virus, viral l atency was established. However, our results suggested that in other i nfected neurons viral replication occurred and virus spread to surroun ding nonneuronal cells and to the central nervous system. This work pr ovides a new model in which the pathogenesis of infections caused by T K-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. ( C) 1994 Academic Press, Inc.