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Journal of Virology, January 2000, p. 965-974, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Replication of Herpes Simplex Virus Type 1 within Trigeminal Ganglia Is Required for High Frequency but Not High Viral Genome Copy Number Latency

Richard L. Thompson1,* and N. M. Sawtell2,*

Department of Molecular Genetics, Microbiology, and Biochemistry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0524,1 and Division of Infectious Diseases, Children's Hospital Medical Center, Cincinnati, Ohio 45229-30392

Received 12 May 1999/Accepted 7 October 1999

The replication properties of a thymidine kinase-negative (TK-) mutant of herpes simplex virus type 1 (HSV-1) were exploited to examine the relative contributions of replication at the body surface and within trigeminal ganglia (TG) on the establishment of latent infections. The replication of a TK- mutant, 17/tBTK-, was reduced by ~12-fold on the mouse cornea compared to the rescued isolate 17/tBRTK+, and no replication of 17/tBTK- in the TG of these mice was detected. About 1.8% of the TG neurons of mice infected with 17/tBTK- harbored the latent viral genome compared to 23% of those infected with 17/tBRTK+. In addition, the latent sites established by the TK- mutant contained fewer copies of the HSV-1 genome (average, 2.3/neuron versus 28/neuron). On the snout, sustained robust replication of 17tBTK- in the absence of significant replication within the TG resulted in a modest increase in the number of latent sites. Importantly, these latently infected neurons displayed a wild-type latent-genome copy number profile, with some neurons containing hundreds of copies of the TK- mutant genome. As expected, the replication of the TK- mutant appeared to be blocked prior to DNA replication in most ganglionic neurons in that (i) virus replication was severely restricted in ganglia, (ii) the number of neurons expressing HSV proteins was reduced 30-fold compared to the rescued isolate, (iii) cell-to-cell spread of virus was not detected within ganglia, and (iv) the proportion of infected neurons expressing late proteins was reduced by 89% compared to the rescued strain. These results demonstrate that the viral TK gene is required for the efficient establishment of latency. This requirement appears to be primarily for efficient replication within the ganglion, which leads to a sixfold increase in the number of latent sites established. Further, latent sites with high genome copy number can be established in the absence of significant virus genome replication in neurons. This suggests that neurons can be infected by many HSV virions and still enter the latent state.

* Corresponding author. Mailing address for R. L. Thompson: University of Cincinnati Medical Center, Department of Molecular Genetics, Microbiology, and Biochemistry, 231 Bethesda Ave., Cincinnati, OH 45267-0524. Phone: (513) 558-0063. Fax: (513) 558-8474. E-mail: Richard.Thompson{at}UC.edu. Mailing address for N. M. Sawtell: Division of Infectious Diseases, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, Ohio 45229-3039. Phone: (513) 636-7880. Fax: (513) 636-7655. E-mail: Sawtn0{at}CHMCC.org.

Journal of Virology, January 2000, p. 965-974, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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