Herpetic retinitis in humans is characterized by a high frequency of bilateral localization. In order to determine the possible mechanisms leading to bilateral retinitis, we studied the pathways by which herpes simplex virus type 1 (HSV-1) is propagated from one retina to the other after intravitreal injection in mice. HSV-1 strain SC16 (90 p.f.u.) was injected into the vitreous body of the left eye of BALB/c mice. Animals were sacrificed 1, 2, 3, 4 and 5 days post-inoculation (p.i.). Histological sections were studied by immunochemical staining. Primary retinitis in the inoculated eye (beginning 1 day p.i.) was followed by contralateral retinitis (in the uninoculated eye) starting at 3 days p.i. Infected neurons of central visual pathway nuclei (lateral geniculate nuclei, suprachiasmatic nuclei and pretectal areas) were detected at 4 days p.i. Iris and ciliary body infection was minimal early on, but became extensive thereafter and was accompanied by the infection of connected sympathetic and parasympathetic pathways. The pattern of virus propagation over time suggests that the onset of contralateral retinitis was mediated by local (non-synaptic) transfer in the optic chiasm from infected to uninfected axons of the optic nerves. Later, retinopetal transneuronal propagation of the virus from visual pathways may have contributed to increase the severity of contralateral retinitis.


Article metrics loading...

Loading full text...

Full text loading...



  1. Apkarian, P., Reits, D. & Spekreijse, H. (1984). Component specificity in albino VEP asymmetry: maturation of the visual system pathway anomaly.Experimental Brain Research 53, 285-294. [Google Scholar]
  2. Atherton, S. S., Pesicka, G. A. & Streilein, J. W. (1987). Retinitis and deviant immune responses following intravitreal inoculation of HSV-1.Investigative Ophthalmology & Visual Science 28, 859-866. [Google Scholar]
  3. Atherton, S. S., Altman, N. H. & Streilein, J. W. (1989). Histopathologic study of herpes virus-induced retinitis in athymic BALB/C mice: evidence for an immunopathogenic process.Current Eye Research 8, 1179-1192.[CrossRef] [Google Scholar]
  4. Babic, N., Mettenleiter, T. C., Flamand, A. & Ugolini, G. (1993). Role of essential glycoproteins gII and gp50 in transneuronal transfer of pseudorabies virus from the hypoglossal nerves of mice.Journal of Virology 67, 4421-4426. [Google Scholar]
  5. Babic, N., Mettenleiter, T. C., Ugolini, G., Flamand, A. & Coulon, P. (1994). Propagation of pseudorabies virus in the nervous system of the mouse after intranasal inoculation.Virology 204, 616-625.[CrossRef] [Google Scholar]
  6. Balan, P., Davis-Poynter, N., Bell, S., Atkinson, H., Browne, H. & Minson, T. (1994). An analysis of the in vitro and in vivo phenotypes of mutants of herpes simplex virus type 1 lacking glycoproteins gC, gE, gI or the putative gJ.Journal of General Virology 75, 1245-1258.[CrossRef] [Google Scholar]
  7. Bienfang, D. (1994). Neuroophthalmology of the pupil and accommodation. In Principles and Practice in Ophthalmology, pp. 2470-2482. Edited by D. A. Albert & F. A. Jakobiec. Philadelphia: W. B. Saunders.
  8. Card, J. P., Whealy, M. E., Robbins, A. K., Moore, R. Y. & Enquist, L. W. (1991). Two alpha-herpesvirus strains are transported differentially in the rodent visual system.Neuron 6, 957-969.[CrossRef] [Google Scholar]
  9. Card, J. P., Whealy, M. E., Robbins, A. K. & Enquist, L. W. (1992). Pseudorabies virus envelope glycoprotein gI influences both neurotropism and virulence during infection of the rat visual system.Journal of Virology 66, 3032-3041. [Google Scholar]
  10. Coen, D. M., Fleming, H. E., Leslie, L. K. & Retondo, M. J. (1985). Sensitivity of arabinosyladenine-resistant mutants of herpes simplex virus to other antiviral drugs and mapping of drug hypersensitivity mutations to the DNA polymerase locus.Journal of Virology 53, 477-488. [Google Scholar]
  11. Coulon, P., Derbin, C., Kucera, P., Lafay, F., Prehaud, C. & Flamand, A. (1989). Invasion of the peripheral nervous system of adult mice by the CVS strain of rabies virus and its avirulent derivative AvO1.Journal of Virology 63, 3550-3554. [Google Scholar]
  12. Culbertson, W. W. & Atherton, S. S. (1993). Acute retinal necrosis and similar retinitis syndromes.International Ophthalmology Clinics 33, 129-143. [Google Scholar]
  13. Dacheux, R. F. & Raviola, E. (1994). Functional anatomy of the neural retina. In Principles and Practice in Ophthalmology. Basic Sciences, pp. 285-309. Edited by D. A. Albert & F. A. Jakobiec. Philadelphia: W. B. Saunders.
  14. Dingwell, K. S., Brunetti, C. R., Hendricks, R. L., Tang, Q., Tang, M., Rainbow, A. J. & Johnson, D. C. (1994). Herpes simplex glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells.Journal of Virology 68, 834-845. [Google Scholar]
  15. Dingwell, K. S., Laurie, L. C. & Johnson, D. C. (1995). Glycoproteins E and I facilitate neuron to neuron spread of herpes simplex virus.Journal of Virology 69, 7087-7098. [Google Scholar]
  16. Dix, R. D., Streilein, J. W., Cousins, S. & Atherton, S. S. (1987). Histopathologic characteristics of two forms of experimental herpes simplex virus retinitis.Current Eye Research 6, 47-52.[CrossRef] [Google Scholar]
  17. Duker, J. S. & Blumenkranz, M. S. (1991). Diagnosis and management of the acute retinal necrosis (ARN) syndrome.Survey of Ophthalmology 35, 327-343.[CrossRef] [Google Scholar]
  18. Enquist, L. W., Dubin, J., Whealy, M. E. & Card, J. P. (1994). Complementation analysis of pseudorabies virus gE and gI mutants in retinal ganglion cell neurotropism.Journal of Virology 68, 5275-5279. [Google Scholar]
  19. Hemady, R., Opremcak, E. M., Zaltas, M., Berger, A. & Foster, C. S. (1989). Herpes simplex type-1 strain influence on chorioretinal disease patterns following intracameral inoculation in Igh-1 disparate mice.Investigative Ophthalmology & Visual Science 30, 1750-1757. [Google Scholar]
  20. Hendrickson, A. E., Wagoner, N. & Cowan, W. M. (1972). An autoradiographic and electron microscopic study of retino-hypothalamic connections.Zeitschrift für Zellforschung und Mikroskopische Anatomie 135, 1-26.[CrossRef] [Google Scholar]
  21. Hill, T. J., Field, H. J. & Blyth, W. A. (1975). Acute and recurrent infection with herpes simplex virus infection in the mouse: a model for studying latency and recurrent disease.Journal of General Virology 28, 341-353.[CrossRef] [Google Scholar]
  22. Holland, G. N. & Executive Committee of the American Uveitis Society (1994). Standard diagnostic criteria for the acute retinal necrosis syndrome. American Journal of Ophthalmology 117, 663–667.[CrossRef] [Google Scholar]
  23. Holland, G. N., Togni, B. I., Briones, O. C. & Dawson, C. R. (1987). A microscopic study of herpes simplex virus in retinopathy in mice.Investigative Ophthalmology & Visual Science 28, 1181-1190. [Google Scholar]
  24. Kelly, J. & Swanson, L. W. (1980). Additional forebrain regions projecting to the posterior pituitary: preoptic region, bed nucleus of the nucleus of the stria terminalis, and zona incerta.Brain Research 197, 1-9.[CrossRef] [Google Scholar]
  25. Kiss, J. Z., Williams, T. H. & Palkovitz, M. (1984). Distribution and projections of cholecystokinin-immunoreactive neurons in the hypothalamic paraventricular nucleus of rat.Journal of Comparative Neurology 227, 173-181.[CrossRef] [Google Scholar]
  26. 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 the Neurological Sciences 54, 149-156.[CrossRef] [Google Scholar]
  27. Kromer, L. F. & Moore, R. Y. (1980). A study of the organization of the locus coeruleus projections to the lateral geniculate nuclei in the albino rat.Neuroscience 5, 255-271.[CrossRef] [Google Scholar]
  28. Kucera, P., Dolivo, M., Coulon, P. & Flamand, A. (1985). Pathways of the early propagation of virulent and avirulent rabies strains from the eye to the brain.Journal of Virology 55, 158-162. [Google Scholar]
  29. Labetoulle, M., Offret, H., Haut, J., Bloch-Michel, E., Ullern, M. & Monin, C. (1995). Acute retinal necrosis syndrome. Retrospective study apropos of 14 eyes in 11 patients.Journal Franais d’Ophtalmologie 18, 777-787. [Google Scholar]
  30. Liu, Y., Minagawa, H., Toh, Y., Ishibashi, T., Inomata, H., Mori, R. & Sakai, Y. (1993). Induction of bilateral retinal necrosis in mice by unilateral intracameral inoculation of a glycoprotein-C deficient clinical isolate of herpes simplex virus type 1.Archives of Virology 129, 105-118.[CrossRef] [Google Scholar]
  31. Lopez, C. (1975). Genetics of natural resistance to herpesvirus infections in mice.Nature 258, 152-153.[CrossRef] [Google Scholar]
  32. Margolis, T. P., LaVail, P., Setzer, P. Y., Dawson, C. R. & LaVail, J. H. (1989). Selective spread of herpes simplex virus in the central nervous system after ocular inoculation.Journal of Virology 63, 4756-4761. [Google Scholar]
  33. Martin, X. & Dolivo, M. (1983). Neuronal and transneuronal tracing in the trigeminal system of the rat using herpes virus suis.Brain Research 273, 253-276.[CrossRef] [Google Scholar]
  34. Metzger, E. E. & Whittum-Hudson, J. A. (1987). The dichotomy between herpes simplex virus type 1-induced ocular pathology and systemic immunity.Investigative Ophthalmology & Visual Science 28, 1533-1540. [Google Scholar]
  35. Moore, R. Y. & Lenn, N. J. (1972). A retinohypothalamic projection in the rat.Brain Research 146, 1-14. [Google Scholar]
  36. Newman, E. A. (1994). Muller cells and the retinal pigment epithelium. In Principles and Practice in Ophthalmology. Basic Sciences, pp. 398-419. Edited by D. A. Albert & F. A. Jakobiec. Philadelphia: W. B. Saunders.
  37. Nieuwenhuys, R., Voogd, J. & van Huijzen, C. (1988). The visual system. In The Human Central Nervous System, pp. 179-196. Edited by R. Nieuwenhuys, J. Voogd & C. van Huijzen. Berlin: Springer-Verlag.
  38. Norgren, R. B., McLean, J. H., Bubel, H. C., Wander, A., Bernstein, D. I. & Lehman, M. N. (1992). Anterograde transport of HSV-1 and HSV-2 in the visual system.Brain Research Bulletin 28, 393-399.[CrossRef] [Google Scholar]
  39. Palay, D. A., Sternberg, P., Davis, J., Lewis, H., Holland, G. N., Mieler, W. F., Jabs, D. A., Drews, C. & Sternberg, P.Jr (1991). Decrease in the risk of bilateral acute retinal necrosis by Acyclovir therapy.American Journal of Ophthalmology 112, 250-255.[CrossRef] [Google Scholar]
  40. Pepose, J. S. & Whittum-Hudson, J. A. (1987). An immunogenetic analysis of resistance to herpes simplex virus retinitis in inbred strains of mice.Investigative Ophthalmology & Visual Science 28, 1549-1552. [Google Scholar]
  41. Pickard, G. E. (1982). The afferent connections of the suprachiasmatic nucleus of the golden hamster with emphasis on the retinohypothalamic projection.Journal of Comparative Neurology 211, 65-83.[CrossRef] [Google Scholar]
  42. Pickard, G. E. (1985). Bifurcating axons of retinal ganglion cells terminate in the hypothalamic suprachiasmatic nucleus and the intergeniculate leaflet of the thalamus.Neuroscience Letters 55, 211-217.[CrossRef] [Google Scholar]
  43. Shimeld, C., Tullo, A. B., Hill, T. J., Blyth, W. A. & Easty, D. L. (1985). Spread of herpes simplex virus and distribution of latent infection after intraocular infection of the mouse.Archives of Virology 85, 175-187.[CrossRef] [Google Scholar]
  44. Sun, N., Cassell, M. D. & Perlman, S. (1996). Anterograde transneuronal transport of herpes simplex virus type 1 strain H129 in the murine visual system.Journal of Virology 70, 5405-5413. [Google Scholar]
  45. Thompson, R. L., Cook, M. L., Devi-Rao, G. B., Wagner, E. K. & Stevens, J. G. (1986). Functional and molecular analyses of the avirulent wild-type herpes simplex virus type 1 strain KOS.Journal of Virology 58, 203-211. [Google Scholar]
  46. Ugolini, G. (1992). Transneuronal transfer of herpes simplex virus type 1 (HSV1) from mixed limb nerves to the CNS. I. Sequence of transfer from sensory motor and sympathetic nerve fibers to the spinal cord.Journal of Comparative Neurology 326, 527-548.[CrossRef] [Google Scholar]
  47. Ugolini, G. (1995). Transneuronal tracing with alpha-herpesviruses: a review of the methodology. In Viral Vectors. Gene Therapy and Neuroscience Applications, pp. 293-317. Edited by M. G. Kaplitt & A. D. Loewy. New York: Academic Press.
  48. Ugolini, G., Kuypers, H. G. J. M. & Simmons, A. (1987). Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV1) from motoneurones.Brain Research 422, 242-256.[CrossRef] [Google Scholar]
  49. Ugolini, G., Kuypers, H. G. J. M. & Strick, P. L. (1989). Transneuronal transfer of herpes virus from peripheral nerves to cortex and brainstem.Science 243, 89-91.[CrossRef] [Google Scholar]
  50. Vann, V. R. & Atherton, S. S. (1991). Neural spread of herpes simplex virus after anterior chamber inoculation.Investigative Ophthalmology & Visual Science 32, 2462-2472. [Google Scholar]
  51. von Szily, A. (1924). Experimentelle endogene Infektionsübertragung von Bulbus zu Bulbus.Klinische Monatsblätter für Augenheilkunde 72, 593-602. [Google Scholar]
  52. Whittum, J. A., McCulley, J. P., Niederkorn, J. Y. & Streilein, J. W. (1984). Ocular disease induced in mice by anterior chamber inoculation of herpes simplex virus.Investigative Ophthalmology & Visual Science 25, 1065-1073. [Google Scholar]
  53. Whittum-Hudson, J. A. & Pepose, J. S. (1987). Immunologic modulation of virus-induced pathology in a murine model of acute herpetic retinal necrosis.Investigative Ophthalmology & Visual Science 28, 1541-1548. [Google Scholar]
  54. Whittum-Hudson, J. A., Farazdaghi, M. & Prendergast, R. A. (1985). A role of T lymphocytes in preventing experimental herpes simplex virus type 1-induced retinitis.Investigative Ophthalmology & Visual Science 26, 1524-1532. [Google Scholar]
  55. Whittum-Hudson, J. A., Merges, J. M. & Field, H. J. (1987). Immunogenicity versus pathogenicity after anterior chamber inoculation of an acyclovir-induced double mutant of HSV-1.Current Eye Research 6, 1459-1470.[CrossRef] [Google Scholar]
  56. Youngstrom, T. Y., Weiss, M. L. & Nunez, A. A. (1987). A retinal projection to the paraventricular nuclei of the hypothalamus in the Syrian hamster (Mesocricetus auratus).Brain Research Bulletin 19, 747-750.[CrossRef] [Google Scholar]

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error