Herpes simplex virus type 1 (HSV-1) establishes latency in neurones of both the central (CNS) and peripheral nervous system and can be used to drive long-term expression of the lacZ reporter gene by insertion of an encephalomyocarditis virus IRES-linked gene 1·5 kb downstream of the latency-associated transcript (LAT) start site. However, the kinetics of LAT promoter (LAP) activity, and its ability to function in all neuronal types within the CNS has not been studied in detail. In order to address these issues, mice were infected via the ear pinna with 2×106 p.f.u. of either SC16-LβA, which contains an IRES-linked lacZ under the control of LAP, or SC16-C3b, which expresses LacZ under the control of the human cytomegalovirus immediate early (HCMV-IE) promoter. Three to five animals from each group were sampled over a time-course from 5 days to 1 year post-infection (p.i.), and brainstem and spinal cord sections were examined histochemically for LacZ expression. We found that HCMV-IE promoter activity could be detected within distinct CNS regions from 5 to 15 days p.i. In contrast, LAP-driven LacZ expression was first detected at 7 days p.i. and persisted for at least 1 year. At times up to 34 days p.i., LAP activity was seen in similar regions of the CNS as those which were positive for HCMV-IE promoter activity during the acute stage of infection. After 34 days, however, the numbers of cells in which the LAP was active decreased and labelled motorneurones were predominantly detected in the facial and hypoglossal nuclei and occasionally also in the ventral spinal cord. These results suggest that following the establishment of latency in the CNS, the efficiency of long-term LAP-mediated gene expression may be influenced by the neuronal cell type in which latency is established.
Arthur, J., Efstathiou, S. & Simmons, A. (1993). Intranuclear foci containing low abundance herpes simplex virus latency-associated transcripts visualised by non-isotopic in situ hybridization.Journal of General Virology74, 1363-1370.[CrossRef][Google Scholar]
Cabrera, C. V., Wohlenberg, C., Openshaw, H., Rey-Mendez, M., Puga, A. & Notkins, A. L. (1980). Herpes simplex virus DNA sequences in the CNS of latently infected mice.Nature288, 288-290.[CrossRef][Google Scholar]
Card, J. P., Rinaman, L., Lynn, R. B., Lee, B.-H., Meade, R. P., Miselis, R. R. & Enquist, L. W. (1993). Pseudorabies virus infection of the rat central nervous system: ultrastructural characterisation of viral replication, transport and pathogenesis.Journal of Neuroscience13, 2515-2539.
[Google Scholar]
Cook, M. L. & Stevens, J. G. (1976). Latent herpetic infections following experimental viraemia.Journal of General Virology31, 75-80.[CrossRef][Google Scholar]
Deatly, A. M., Spivack, J. G., Lavi, E., O’Boyle, D. R. & Fraser, N. W. (1988). Latent herpes simplex virus type 1 transcripts in peripheral and central nervous system tissues of mice map to similar regions of the viral genome.Journal of Virology62, 749-756.
[Google Scholar]
Engel, J. P., Madigan, T. C. & Peterson, G. M. (1997). The transneuronal spread phenotype of herpes simplex virus type 1 infection of the mouse hind footpad.Journal of Virology71, 2425-2435.
[Google Scholar]
Enquist, L. W., Husak, P. J., Banfield, B. W. & Smith, G. A. (1998). Infection and spread of alphaherpesviruses in the nervous system.Advances in Virus Research51, 237-347.
[Google Scholar]
Fitzgerald, M. J. T. (1994).Neuroanatomy: Basic and Clinical. London: Bailliére Tindall.
Gressens, P. & Martin, J. R. (1994). In situ polymerase chain reaction: localisation of HSV-2 DNA sequences in infections of the nervous system.Journal of Virological Methods46, 61-83.[CrossRef][Google Scholar]
Hill, T. J., Field, H. J. & Blyth, W. A. (1975). Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease.Journal of General Virology28, 341-353.[CrossRef][Google Scholar]
Holstege, G., Kuypers, H. G. J. M. & Dekker, J. J. (1977). The organisation of the bulbar fibre connections to the trigeminal, facial and hypoglossal motor nuclei. II. An autoradiographic tracing study in cat.Brain100, 265-286.[CrossRef][Google Scholar]
Huang, Q. S., Valyi-Nagy, T., Kesari, S. & Fraser, N. W. (1997). β-Gal enzyme activity driven by the HSV LAT promoter does not correspond to β-Gal RNA levels in mouse trigeminal ganglia.Gene Therapy4, 797-807.[CrossRef][Google Scholar]
Kesari, S., Lee, V. M.-Y., Brown, S. M., Trojanowski, J. Q. & Fraser, N. W. (1996). Selective vulnerability of mouse CNS neurons to latent infection with a neuroattenuated herpes simplex virus-1.Journal of Neuroscience16, 5644-5653.
[Google Scholar]
Knotts, F. B., Cook, M. L. & Stevens, J. G. (1973). Latent herpes simplex virus in the central nervous system of rabbits and mice.Journal of Experimental Medicine138, 740-744.[CrossRef][Google Scholar]
Kristensson, K. (1970). Morphological studies of the neural spread of herpes simplex virus to the central nervous system.Acta Neuropathologica16, 54-63.[CrossRef][Google Scholar]
Kristensson, K., Nennesmo, I., Persson, L. & Lycke, E. (1982). Neuron to neuron transmission of herpes simplex virus – transport of virus from skin to brainstem nuclei.Journal of Neurological Sciences54, 149-156.[CrossRef][Google Scholar]
Lachmann, R. H. & Efstathiou, S. (1997). Utilization of the herpes simplex virus type 1 latency-associated regulatory region to drive stable reporter gene expression in the nervous system.Journal of Virology71, 3197-3207.
[Google Scholar]
Lachmann, R. H., Brown, C. & Efstathiou, S. (1996). A murine RNA polymerase promoter inserted into the herpes simplex virus type 1 genome is functional during lytic, but not latent, infection.Journal of General Virology77, 2575-2582.[CrossRef][Google Scholar]
Lachmann, R. H., Sadarangani, M., Atkinson, H. R. & Efstathiou, S. (1999). An analysis of herpes simplex virus gene expression during latency establishment and reactivation.Journal of General Virology80, 1271-1282.
[Google Scholar]
LaVail, J. H., Zhan, J. & Margolis, T. P. (1990). HSV (type 1) infection of the trigeminal complex.Brain Research514, 181-188.[CrossRef][Google Scholar]
Maggioncalda, J., Mehta, A., Su, Y. H., Fraser, N. W. & Block, T. M. (1996). Correlation between herpes simplex virus type 1 rate of reactivation from latent infection and the number of infected neurones in trigeminal ganglia.Virology225, 72-81.[CrossRef][Google Scholar]
Margolis, T. P., LaVail, J. H., Setzer, P. Y. & Dawson, C. R. (1989). Selective spread of herpes simplex virus in the central nervous system after ocular inoculation.Journal of Virology63, 4756-4761.
[Google Scholar]
Mehta, A., Maggioncalda, J., Bagasra, O., Thikkavarapu, S., Saikumari, P., Valyi-Nagy, T., Fraser, N. W. & Block, T. M. (1995). In situ DNA PCR and RNA hybridization detection of herpes simplex virus sequences in trigeminal ganglia of latently infected mice.Virology206, 633-640.[CrossRef][Google Scholar]
Noback, C. R. & Demarest, R. J. (1984).The Human Nervous System – Basic Principles of Neurobiology, 3rd edn. New York: McGraw-Hill.
Paxinos, G. & Watson, C. (1986).The Rat Brain in Stereotaxic Co-Ordinates, 2nd edn. London: Academic Press.
Ramakrishnan, R., Levine, M. & Fink, D. J. (1994). PCR-based analysis of herpes simplex virus type 1 latency in the rat trigeminal ganglion established with a ribonucleotide reductase-deficient mutant.Journal of Virology68, 7083-7091.
[Google Scholar]
Roizman, B. & Sears, A. E. (1996). Herpes simplex viruses and their replication, chapter 72. In Fields Virology, 3rd edn. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia & New York: Lippincott-Raven.
Sawtell, N. M. & Thompson, R. L. (1992). Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency.Journal of Virology66, 2157-2169.
[Google Scholar]
Speck, P. G. & Simmons, A. (1991). Divergent pathways of productive and latent infection with a virulent strain of herpes simplex virus type 1.Journal of Virology65, 4001-4005.
[Google Scholar]
Speck, P. G. & Simmons, A. (1992). Synchronous appearance of antigen-positive and latently infected neurons in spinal ganglia of mice infected with a virulent strain of herpes simplex virus.Journal of General Virology73, 1281-1285.[CrossRef][Google Scholar]
Stevens, J. G., Wagner, E. K., Devi-Rao, G. B., Cook, M. L. & Feldman, L. T. (1987). RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons.Science235, 1056-1059.[CrossRef][Google Scholar]
Stroop, W. G., Rock, D. L. & Fraser, N. W. (1984). Localization of herpes simplex virus in the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by in situ hybridization.Laboratory Investigation51, 27-38.
[Google Scholar]
Thompson, R. L. & Sawtell, N. M. (1997). The herpes simplex virus type 1 latency-associated transcript gene regulates the establishment of latency.Journal of Virology71, 5432-5440.
[Google Scholar]
Tullo, A. B., Shimeld, C., Blyth, W. A., Hill, T. J. & Easty, D. L. (1982). Spread of virus and distribution of latent infection following ocular herpes simplex in the non-immune and immune mouse.Journal of General Virology63, 95-101.[CrossRef][Google Scholar]
Ugolini, G., Kuypers, H. G. J. M. & Simmons, A. (1987). Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones.Brain Research422, 242-256.[CrossRef][Google Scholar]
Ugolini, G., Kuypers, H. G. J. M. & Strick, P. L. (1989). Transneuronal transfer of herpes virus from peripheral nerves to cortex and brainstem.Science243, 89-91.[CrossRef][Google Scholar]
Wagner, E. K. & Bloom, D. C. (1997). Experimental investigation of herpes simplex virus latency.Clinical Microbiological Reviews10, 419-443.
[Google Scholar]
Wildy, P., Field, H. J. & Nash, A. A. (1982). Classical herpes latency revisited. In Virus Persistence Symposium 33, pp. 133-167. Edited by B. W. J. Mahy, A. C. Minson & G. K. Darby. Cambridge: Cambridge University Press.