Synergistic effects on ganglionic herpes simplex virus infections by mutations or drugs that inhibit the viral polymerase and thymidine kinase.
Herpes simplex virus encodes proteins, such as DNA polymerase, that are essential for its replication and proteins, such as thymidine kinase, that are not essential for replication in cell culture, but are important for pathogenesis in animal models. However, certain mutations affecting these proteins exert little or no effect on replication or pathogenesis. We tested the effects of combining two such mutations--one that alters DNA polymerase and one that decreases but does not abolish thymidine kinase activity--on replication in cultured cells and on acute and latent infections in mice. The double mutant replicated similarly to the single mutants and wild-type virus both in cell culture and acutely in the mouse eye. However, it was severely impaired for acute replication in trigeminal ganglia and for reactivatable latent infections. This impairment depended upon the polymerase mutation. Similarly, although Ro 31-5140, a thymidine kinase inhibitor, did not potentiate the antiviral effects of phosphonoacetic acid, a polymerase inhibitor, in cell culture, the two drugs in combination substantially inhibited viral reactivation from latency at concentrations that had little or no effect when used singly. These synergistic effects may have implications for viral functions during pathogenesis and for antiviral chemotherapy.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
J
J
Jacobson
M
M
Kramer
F
F
Rozenberg
A
A
Hu
D M
DM
Coen
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002522:Chlorocebus aethiops; D004279:DNA, Viral; D005724:Ganglia / Q000821:virology*; D015751:Genes, pol; D006561:Herpes Simplex / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors; D009930:Organic Chemicals; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; D009930:Organic Chemicals; C091564:Ro 31-5140; D013937:Thymidine Kinase