Herpes Simplex Virus In Ganglia Research Articles

Herpes simplex virus infection of murine sensory ganglia induces proliferation of neuronal satellite cells.

Herpes simplex virus (HSV) is a virtually ubiquitous human pathogen that, following cutaneous infection, latently infects neurons of sensory ganglia. Satellite cells (SCs) ensheath and provide metabolic support for these neurons, and could potentially participate in controlling HSV disease. Although SCs are restrictive for HSV replication, hypercellularity of non-neuronal cells in ganglia is prominent during HSV infection in animal models. SCs proliferate in response to trauma, e.g. nerve cut or crush, but it is not known if proliferation occurs in response to viral infection. To address this issue, cell proliferation, measured by bromodeoxyuridine (BrdU) uptake, and immune infiltrate, measured by CD45 labelling, were examined during acute infection in a mouse model. Because SCs do not express CD45, the BrdU(+) CD45(-) cell subset represents the proliferating SC population. We report that during acute ganglionic HSV infection there is a substantial increase in SC numbers. We suggest that SC proliferation in response to HSV infection may occur in order to facilitate neuronal survival.

Granzyme A, a noncytolytic component of CD8(+) cell granules, restricts the spread of herpes simplex virus in the peripheral nervous systems of experimentally infected mice.

Control of ganglionic herpes simplex virus (HSV) infection depends on CD8(+) cells but not on the death of infected neurons. Primarily, perforin and granzyme B mediate CD8(+) cell cytotoxicity, whereas the in vivo functions of granzyme A, a third granule protein, are unknown. Here, it is shown that granzyme A restricts the interneuronal spread of HSV and significantly influences ganglionic virus load.

Anti-CD8 treatment alters interleukin-4 but not interferon-gamma mRNA levels in murine sensory ganglia during herpes simplex virus infection. Brief report.

Clearance of herpes simplex virus (HSV) from sensory ganglia of infected mice is dependent on CD8(+) cells but not on the death of infected neurons. The mechanism of action of CD8(+) cells in HSV infected ganglia is therefore unknown. The determine which cytokines might be involved in the CD8(+) cell dependent response to ganglionic HSV infection, IL-2, IL-4, IL-6, IL-10, and IFN-gamma mRNA levels were measured in infected ganglia from immunocompetent and anti-CD8 treated mice. Anti-CD8 treatment increased the abundance of mRNA encoding IL-4, and, to a lesser extent, IL-2, and IL-6. Significantly, IFN-gamma mRNA was not affected.

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, suchas 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.

Herpes simplex virus: Molecular biology and the possibility of corneal latency

Herpes simplex virus (HSV) is known to be latent in ganglionic neurons. Over the past eight years, a series of reports have described the isolation of HSV after organ culture of human corneas that had been removed in the course of penetrating keratoplasty. None of the corneas showed any clinical signs of active herpetic disease immediately before keratoplasty. Studies in rabbits and mice confirmed that HSV can be recovered from corneas by organ culture long after primary infection has subsided. Recently, sophisticated techniques of molecular biology, such as specific DNA or RNA probes, have been used to detect HSV nucleic acids in the cornea. The crux of the matter is whether the virus recovered from or detected in the cornea is 1) truly latent in cell populations that are nonneuronal; 2) resident in the cornea, replicating at a slow rate; or 3) newly arrived in the cornea following ganglionic reactivation. The evidence suggests that a guarded case can be made for limited HSV latency within corneal cells. HSV corneal latency would allow for reactivation, replication, and the immune response to occur in the absence of ganglionic HSV reactivation. Such a localized phenomenon has not, however, been demonstrated to occur clinically.

Role of Herpes simplex Virus Thymidine Kinase Expression in Viral Pathogenesis and Latency

Herpes simplex virus (HSV) thymidine kinase (TK) expression and the HSV TK gene have been evaluated in studies of gene control, as well as in animal and human studies of viral pathogenesis, including HSV latency. In investigations of the biological role of HSV TK, enzyme expression was noted to be important for HSV infection of nonreplicating cells in culture; and, in experimental animal studies, HSV TK was shown to be important for in vivo latent infection of sensory ganglion neurons. Latency in these studies was determined by the ability of HSV to reactivate from sensory ganglion explants. In recent studies, investigators sought to determine whether the role HSV TK expression plays in latency is primarily in the establishment and maintenance of latency or in the reactivation process. Following infection of experimental animals with HSV TK-deficient mutants, the presence of HSV in ganglia was detected in complementation, rescue, and molecular biological studies. Results suggest that HSV TK expression may be important for HSV reactivation from latency. This was supported by in situ hybridization investigations. In the latter studies, HSV latency associated transcript (LAT) was present in ganglion neurons, although reactivation of HSV from such ganglia was defective. LAT-expressing, reactivation-defective infections established by TK mutants of HSV are considered examples of incomplete latency. From the present review, it appears that HSV TK expression, particularly TK expression of HSV-1, is important for the reactivation of latent HSV infection of sensory ganglion neurons, probably because of limited neuronal TK expression and absent replication capacity of these cells.

HSV-induced reactivation: contribution of epinephrine after corneal iontophoresis.

A modified, bilateral iontophoresis technique was used to evaluate herpes simplex virus (HSV) reactivation and epinephrine distribution and concentration in full-thickness corneas and in trigeminal ganglia of rabbits. Infectious virus was recovered from 58% of epinephrine-induced eyes 24-96 hours after iontophoresis. A histochemical adrenochrome oxidation method localized epinephrine exclusively in the corneal epithelium and anterior stromal lamellae after iontophoresis. Epinephrine introduced iontophoretically into the corneal epithelium and stroma did not reach the ganglion level as detected by the assay. Radiometric-enzymatic assay of corneal and ganglionic tissues demonstrated a transient increase in total corneal catecholamine levels from an average of 417 micrograms to an average of 778 micrograms ; concentrations returned to approximate control values 24 hours after iontophoresis. Ganglion total catecholamine levels increased from an average of 606 micrograms to an average of 1211 micrograms for a 12-hour period and remained elevated at 24 hours after iontophoresis. Epinephrine acting directly on the corneal epithelium and epinephrine metabolites at the ganglion level could act synergistically to induce ocular and ganglionic HSV reactivation.

In vitro effect of ( E)-5-(2-bromovinyl)-2′-deoxyuridine, 5′-amino-5-iodo-2′,5′-dideoxyuridine and 2-deoxy- d-glucose on latent ganglionic herpes simplex virus infection

( E)-5-(2-Bromovinyl)-2′-deoxyuridine (BVDU) and 5′-amino-5-iodo-2′,5′-dideoxyuridine AIdUrd) blocked the reactivation of latent ganglionic herpes simplex virus in vitro. Furthermore, BVDU, but not AIdUrd, blocked the multiplication of reactivated latent virus and transiently suppressed emergence of reactivated virus from the sensory ganglia after removal of drug from the medium. 2-Deoxy- d-glucose (2-DG) neither prevented the in vitro reactivation of latent virus nor blocked the further multiplication of reactivated latent virus.

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.

Acyclovir therapy for the orofacial and ganglionic HSV infection in hairless mice.

Acyclovir (ACV) therapy, topical or systemic, showed a significantly high therapeutic efficacy for facial Herpes Simplex Virus (HSV) infection in hairless mice. When topical ACV treatment was initiated very early, i.e., three h post-inoculation, the number of mice with latent HSV infection in their trigeminal ganglia was significantly reduced. These results indicate that ACV clearly merits further investigation as an antiviral agent for therapy of orofacial HSV infections.

Acyclovir in Oral and Ganglionic Herpes Simplex Virus Infections

The local and trigeminal ganglionic therapeutic efficacy of two topical and systemic antiviral drugs was studied in mouse lips inoculated with herpes simplex virus type 1 after thermal injury. Application of topical 3% acylovir (acycloguanosine) ointment three times daily for four days completely blocked the replication of virus in the lips, and the healing process was greatly accelerated compared with that in placebo-treated infected controls. However, neither the healing process nor the viral replication was influenced by similar therapy with 3% vidarabine ointment. When given systemically for four days, starting one day after inoculation, acyclovir (40-60 mg/kg per day) and vidarabine (50 mg/kg per day) significantly reduced the clinical manifestations on the lips and viral titers of cultures obtained from the lips. Establishment of viral latency in the trigeminal ganglion was significnatly inhibited by systemic acyclovir (60 mg/kg per day), whereas systemic vidarabine (50 mg/kg per day) was ineffective. These data suggest that acyclovir may be one of the most promising antiviral agents for the management of oral herpes viral infections and trigeminal ganglionic latency of virus as demonstrated in the mouse model.

Latent herpes simplex virus in ganglia of mice after primary infection and reinoculation at a distant site

Herpes simplex virus (HSV)-infected hairless mice with evidence of latent infection in spinal ganglia did not develop latent HSV infections in trigeminal ganglia upon reinfection in the oro-facial area. HSV-infected and PAA-treated mice without evidence of latent HSV infection in spinal ganglia were resistant to reinfection in the lumbar region, but not to that performed in the oro-facial area.