Differential accumulation of herpes simplex virus type 1 latency-associated transcripts in sensory and autonomic ganglia.

We have analyzed the capacity of sensory and autonomic ganglia to demonstrate latency-associated transcripts (LATs) following inoculation of the anterior chamber of the mouse eye with Herpes simplex virus type 1 (HSV-1). In autonomic ganglia, the number of LAT-containing neurons decreased 50-fold or more from the acute to the latent phase, while in the trigeminal ganglion, the decrease was less than 2-fold. The decrease in autonomic ganglia could not be related to destruction of neurons expressing LATs, since these ganglia harbored substantial amounts of viral DNA. The data demonstrate that during the latent phase of the infection, accumulation of LATs varies depending on the type of infected neuron and suggest that some neurons may harbor a latent infection in the absence of LAT expression.

Ganglionic herpes simplex and systemic acyclovir.

The therapeutic and systemic effects of acyclovir on ganglionic herpes simplex virus (HSV) in mice were studied by varying the duration of treatment and the time of removal of ganglia for co-cultivation after treatment had ended. When treatment was started three hours after infection, it had a significant therapeutic effect even when the ganglionic culture was delayed 17 days after the end of acyclovir therapy. When treatment was started 24 hours after infection, it had no significant effect under the same circumstances. The treatment of established latent ganglionic HSV for 15 days with acyclovir had a significant therapeutic effect compared with control mice when ganglia were cultured two days after treatment had ended, but this effect was lost by ten and 21 days after the end of therapy. This indicates that acyclovir has a transient suppressive effect on part of the viral ganglionic reservoir, but it also indicates that these titers quickly reestablish themselves with the removal of drug therapy.

6-Hydroxydopamine potentiates acute herpes simplex virus infection of the superior cervical ganglion in mice.

Treatment of mice with 6-hydroxydopamine increased herpes simplex virus replication in the superior cervical ganglion while it decreased the subsequent prevalence of latent infection. Preganglionic neurectomy failed to block this effect. These observations suggest that intrinsic neural events modify the outcome of viral infections of the nervous system.

Herpetic eye disease in rabbits after inoculation of autonomic ganglia.

Since herpes simplex virus (HSV) can cause persistent infection of autonomic ganglia of both humans and experimentally infected animals, we followed the pattern of eye disease and viral growth after HSV inoculation of one superior cervical ganglion in rabbits. Of 27 inoculated animals, eye disease or detectable virus developed in 18. Anterior uveitis was the most common clinical manifestation (94%), but conjunctivitis and dendritic keratitis were also frequent (60%). All 12 uveal-retinal specimens tested and five of seven ipsilateral superior cervical ganglia had detectable virus. If recurrent herpetic iritis in humans is associated with persistent infection of the superior cervical ganglion, autonomic mediators might trigger episodes of virus shedding. In patients with herpetic iritis, then, the use of epinephrine and other adrenergic agonists or antagonists should be avoided.

The polypeptide and the DNA restriction enzyme profiles of spontaneous isolates of herpes simplex virus type 1 from explants of human trigeminal, superior cervical and vagus ganglia.

Analysis of the infected cell polypeptides and the DNA restriction profiles of 31 HSV-1 isolates from the trigeminal, superior cervical and vagus ganglia from 17 individuals (12 U.S.A., 2 Japanese, 3 Norwegian) could be classified as 15 different virus strains. With the exception of the three Norwegian isolates which gave identical profiles, virus isolates from the ganglia of different individuals could all be distinguished from one another. In contrast virus isolates from the trigeminal, superior cervical and vagus ganglia of the same individual, or virus isolates from the left and right ganglia of the same individual or multiple isolates from different explants of a single ganglion were indistinguishable. In conclusion, a single virus strain infects each individual initially and virus descended from this event subsequently infects and becomes latent in different cells of the same ganglion as well as in different ganglia.

Route of infection, systemic host resistance, and integrity of ganglionic axons influence acute and latent herpes simplex virus infection of the superior cervical ganglion.

The character of acute and latent herpes simplex virus (HSV) infection of the superior cervical ganglion (SCG) in mice depended on the route by which the virus reached the ganglion, the level of systemic host resistance, and the integrity of postganglionic nerves. Prevention of ganglionic infection by postganglionic neurectomy carried out before intraocular (i.o.) virus challenge established the importance of the neural route in the development of SCG infection. However, hematogenous virus dissemination also led to SCG infection although with reduced frequency compared to that with i.o. inoculation. Enhanced host systemic antiviral resistance had two divergent effects on ganglionic infection depending on the dose and timing of virus inoculation. Thus, both acute and latent ganglionic infections were concomitantly reduced when resistant C57B1/6 mice were challenged with low doses of virus or when less resistant BALB/c mice were actively immunized 1 week before virus challenge. On the other hand, when resistant mice were challenged with high doses of virus or when either active or passive (antibody) immunization was delayed long enough to assure viral access to the ganglion, intraganglionic viral replication during the acute phase of infection was reduced, but the prevalence of subsequent latent infection was either unaffected or actually enhanced. Postganglionic neurectomy, performed after virus had reached the ganglion, altered the course of SCG infection in a direction opposite that of immunization, augmenting the acute phase of viral replication while reducing latency. In athymic nude mice and mice immunosuppressed with cyclophosphamide, intraganglionic viral replication was prolonged. These results emphasize that host factors both extrinsic and intrinsic to the SCG modify the course of ganglionic infection.

Reactivation of latent herpes simplex virus infection of the autonomic nervous system by postganglionic neurectomy.

Latent herpes simplex virus infection of the superior cervical autonomic ganglion was reactivated in vivo by postganglionic neurectomy. Two methods were used to demonstrate viral reactivation: (i) recovery of infectious herpes simplex virus in ganglion homogenates and (ii) acceleration of virus expression in ganglion explants in culture. Both the percentage of mice exhibiting reactivated ganglion infection and the viral titers detected in ganglia increased when neurectomized mice were treated with cyclophosphamide. Antithymocyte serum treatment prolonged the time course over which neurectomy-induced virus could be detected, but neither antithymocyte serum nor cyclophosphamide reactivated herpes simplex virus in the absence of neurectomy. These results demonstrate that postganlionic neurectomy provides a specific stimulus for herpes simplex virus reactivation and that cell-mediated immune defense are involved in the highly efficient elimination of reactivated virus from the ganglion in vivo.

Ultrastructure and function in sympathetic ganglia isolated from rats infected with pseudorabies virus.

(1) After inoculation of the pseudorabies virus in the anterior chamber of the eye of the rat, virions can be found only in the neurons of the superior cervical sympathetic ganglion and in the sensory ganglion of the fifth nerve on the inoculated side. Other nervous structures--central or peripheral--are not infected. (2) It is shown that the retrograde axonal flow carries the virus from the eye to the sympathetic neurons. (3) The ultrastructure of the infected neuron has been studied at various intervals after inoculation and at different stages of the viral replication. (4) Excised infected ganglia in vitro show a spontaneous electrophysiological activity that can be recorded on both the post- and preganglionic nerve. Such an activity has never been seen in normal excised ganglion of rat. (5) The shape and frequency of the electrophysiological discharges recorded on the postganglionic nerve have been analyzed at various intervals after inoculation. (6) Correlations established between the ultrastructure, the effect of various drugs and the electrophysiological activity permit the proposal of various hypothesis about the abnormal activity of the infected neurons.

Herpesvirus in sensory and autonomic ganglia after eye infection.

In herpesvirus hominis (HVH) infections, virus harbored in the sensory ganglia is now thought to be the main source of recurrent infection at peripheral sites. Experimental HVH infection of the external eye in rabbits produces an acute infection and then latent infection of the trigeminal ganglion. In this study, acute infection of the automatic ganglia serving the eye (superior cervical and ciliary) as well as trigeminal ganglia occurred after HVH inoculation of rabbits' corneas with a herpes type 1 strain (RE). Latent virus infection was detected in the trigeminal ganglion of one of five animals tested six months after initial infection. Since the superior cervical and other autonomic ganglia serving the eye become infected during acute herpes simplex virus infection of the external eye in rabbits, it is possible that these ganglia are also sources of reinfection in recurrent herpetic disease of the eye. Following the initial eye disease with this virus strain, HVH shedding could not be demonstrated even after induction attempts by topically applied epinephrine or systemic use of cyclophosphamide. Thus, establishment of latent HVH infection in the ganglia and chronic shedding of virus into the external eye is not a constant feature of this animal model, but may depend on the specific strain of herpesvirus used.

Peripheral nervous system involvement in experimental tuberculosis.

Following intravenous injection of mycobacteria in the mouse the bacilli are regularly found in the peripheral nervous system after the 5th day. The peripheral nerves and autonomic ganglia are involved at the level of the perineural cells and the sheath of Schwann. When the organisms are of low virulence (BCG, Mycobacterium intracellulare) the development of the nodules is limited. In the case of a virulent strain (Ravenel) extensive granulomas are found but epitheloid cells, always found in other organs, are constantly absent. In animals previously immunized, the bacilli seem to implant themselves as in the controls, but multiply more slowly; the nodules are more infrequent and the lymphoid infiltration appears earlier with the multiplication of interstitial cells.