Herpes simplex virus latency in the rabbit trigeminal ganglia: ganglionic superinfection.

It has been confirmed and further documented that infection of the rabbit cornea with the E-43 strain of HSV-1 precludes superinfection of the corresponding trigeminal ganglia by another HSV strain, i.e., the challenging virus does not establish latency and can not be recovered from the ganglia. It was shown that after primary infection, a state of resistance is established in the neuronal cells of the ganglia, and although the challenging strain reaches the ganglia, it does not cause discernible acute infection, and does not displace the resident virus in the ganglia. This protection was present 6 months after primary infection, was independent of immune factors such as circulating or secretory antibodies, and was localized to the point of entry of the primary infecting strain and the sensory neurons that innervate that site. The smallest inoculum that provided protection from ganglionic superinfection was that which produced overt disease in the eye, although different degrees of disease resulted from varying inocula above this minimum. Asymptomatic primary infections produced by subminimal inocula of the E-43 strain or by the HSV recombinant strain, F(MP)F, which is avirulent for the rabbit eye, protected against severe disease and death, but the degree of protection against ganglionic superinfection was variable and depended on the time of challenge. These findings suggest that susceptible neurons in the trigeminal ganglion, when "occupied" by an infecting strain, cannot be superinfected by a second strain.

Virus chemotherapy: antiviral drugs and interferon.

Early antiviral drugs, such as idoxuridine and vidarabine, are less effective than newer drugs, such as trifluorothymidine and acyclovir. However, trifluorothymidine is less subject to the development of drug-resistant strains and can be administered topically as a clear drop, which increases patient compliance. Acyclovir has low toxicity and is selective for virus-infected cells because it must be phosphorylated by the viral thymidine kinase to become active. However, drug-resistant strains are produced relatively easily in vitro and may also develop in man with long-term use. To date, no antiviral drug alone has been shown to be effective in the treatment of stromal disease, and no antiviral drug is able to eradicate virus latent in the ganglia and thereby prevent recurrent herpetic infections. Combinations of antiviral drugs and antiviral drugs and interferon are being tested for enhanced efficacy in the treatment of ocular herpetic disease, and for prophylactic effects. The development of recombinant interferons has reduced cost and increased availability, but the effects of the 'manufactured' interferon are not identical to those of natural human leukocyte interferon in all experimental situations.

Analysis of viral DNA in isolates from patients with recurrent herpetic keratitis.

Isolates were obtained from 10 patients with recurrent herpes simplex type 1 infection of the eye, lids, or mouth. The viral DNA of successive isolates from each patients was analyzed by restriction endonuclease fingerprinting. Evaluation of the DNA banding patterns of all isolates by means of two different enzymes, performed in a masked fashion, demonstrated that all of the isolates from any one patient had the same genetic makeup. These results indicate that recurrent herpes infections of the eye and face in humans are caused not by unrelated, serial infections but rather by reactivation of the same latent virus that remains in the ganglion over a period of years.

Oral antiviral drugs in experimental herpes simplex keratitis.

Chronic oral administration of acyclovir or bromovinyl deoxyuridine to rabbits did not prevent recurrence of virus shedding or clinical corneal disease, nor did it alter the clinical course of recurrences of ocular herpetic disease or result in the appearance of resistant virus in tears.

Herpes simplex keratitis.

Avirulent strains of herpes simplex type 1 (HSV-1) infect and shed and colonize the ganglia in rabbits. This primary infection reduces the severity of subsequent infection by virulent virus and prevents ganglionic colonization by even very virulent neurotropic virus. Only a small proportion of the human population known to be infected with HSV-1 develops clinical disease. It is possible that the severity and likelihood of recurrence of this disease is determined by the virulence of the original infecting HSV-1 strain. In addition, there is evidence for differences in antigenicity among the various virus strains, and it may be that the development of stromal disease is related to the host response to these differences. Among the drugs generally available for the treatment of herpetic disease, trifluridine is currently the newest and most effective. Other compounds, such as acyclovir and BVDU, are being developed; because these drugs are specific for the virus and do not interfere with the metabolic processes of normal cells, they have a very low toxicity. Also, it may be that these compounds have a combined effect with other antiviral agents, such as vidarabine, increasing their potency against stromal disease and iritis.

Initial herpes simplex virus type 1 infection prevents ganglionic superinfection by other strains.

The ganglia of rabbits infected with a relatively benign strain of herpesvirus (E-43) and challenged with either of two virulent neurotrophic strains (MP or McKrae) were found to be colonized only by the initial benign infecting strain. Primary infection with the E-43 strain resulted in milder disease when the animals were infected with MP or McKrae strains and also prevented colonization of the ganglion by these strains. Neutralization with anti-glycoprotein C, plaque morphology, cytopathic effects, reconstruction experiments, and restriction endonuclease analysis indicated that the virus recovered from the ganglion was the initial infecting E-43 strain; no traces of the challenging MP and McKrae strains were found. The challenging McKrae strain was shed for several weeks in a few animals, but the virus isolated from the trigeminal ganglia of these animals was the primary infecting E-43 strain. These results suggest that initial infection with a relatively benign strain of herpesvirus may prevent superinfection of the ganglion (but not necessarily the end organ) by highly virulent herpes simplex virus strains and could have significant implications in the consideration of immunization against this disease in humans.

Ocular disease pattern induced by herpes simplex virus is genetically determined by a specific region of viral DNA.

The pattern of ocular disease produced in the rabbit eye by HSV-1 (F) and HSV-1(MP) strains and recombinants F(MP)A, F(MP)B, F(MP)C, F(MP)D, F(MP)E, and F(MP)F was studied. The characteristics of ocular herpetic disease such as morphology of dendritic ulcers, severity of epithelial disease and incidence and duration of stromal disease produced in the rabbit eye are genetically determined by the virus strain. Our studies show that transfer of a defined part of the genome of the stromal disease-producing virus, HSV-1(MP), to the genome of an epithelial disease-producing virus, HSV-1(F), yielded recombinants with one or more of the disease characteristics of the donor strain. Specifically, recombinant F(MP)D produced lesions characteristic of the donor HSV-1(MP) strain; recombinants F(MP)C and F(MP)E produced stromal disease approaching the severity of the disease produced by the donor HSV-1(MP) strain, and only recombinants F(MP)A and F(MP)B retained the typically elongate lesions of the recipient HSV-1(F), whereas the recombinant strain F(MP)F produced no disease. The viral functions pertaining to the ocular disease pattern map between 0.70 and 0.83 map units in HSV-1 DNA within the BglII F DNA fragment. The pattern of stromal disease is independent of the production of glycoprotein C and fusion of HEp-2-infected cells. The functions relating to these aspects of ocular disease segregate but are closely linked.