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Herpes simplex virus (HSV) infection induces numerous electrophysiological and microscopic changes in neurons in vitro. To investigate the effect of HSV infection on in vivo neuronal activity, we induced an acute, latent and reactivated HSV infection of the trigeminal ganglia of guinea pigs through orofacial HSV inoculation and studied its effect on the trigeminal jaw-opening reflex of anesthetized guinea pigs. During the acute viral infection period both the threshold for elicitation of the reflex, and the latency to the onset of the reflex response were increased. During the latent viral infection in the trigeminal ganglia, the jaw-opening reflexes in the viral infected animals were not different from those of non-infected control animals. However, reactivation of the latent viral infection in these animals resulted in increases in both the threshold and latency of the jaw-opening reflex. These changes were similar to those found in animals with the acute viral infection. These results indicate that acute or reactivated latent HSV infection of the nervous system results in functional changes in the reflex pathways involving the trigeminal gasserian ganglia and brainstem neurons harboring infectious HSV-1.

This report is concerned with the capacities of aciclovir to protect mice challenged intracerebrally with multiple lethal doses of type 1 herpes simplex virus and to control multiplication of this virus in the brain. With treatment initiated 12 h after inoculation and continued for 4 consecutive days, aciclovir administered subcutaneously in daily doses ranging from 40 to 100 mg/kg led to 21-day survival rates of from 33 to 73% and reduced virus titers by 1 to (1/2) x 4 logs on postchallenge day 8. The therapeutic accomplishments of the 100-mg/kg doses of aciclovir were comparable to those of 1,000-mg/kg doses of vidarabine (9-beta-d-arabinofuranosyladenine); however, as measured by impact on body weight, aciclovir was better tolerated than vidarabine at these similarly effective doses.

This study examined the effect of 7, 12-dimethyl-benz(a)anthracene (DMBA), polycyclic aromatic hydrocarbon carcinogen, on pathologic changes in buccal pouch mucosa of hamsters with latent herpes simplex virus type 1 (HSV-1) infections in their trigeminal ganglia. Of the pouches receiving DMBA treatment, the average number of tumors per pouch was significantly higher (p less than 0.01) in pouches of animals with HSV-1 infections as compared to those that received DMBA only. Of the pouches receiving DMBA, the average cumulative tumor diameter (the sum of the tumor diameters in each group divided by the number of pouches in that group) was notably greater in animals with latent HSV-1 than in animals that had not been infected; however, this difference was not significant. The DMBA-treated hamsters that had latent infections also displayed a higher severity and prevalence of histopathologic changes in their pouch mucosa. This study indicates that latent HSV-1 and DMBA show synergism in the development of tumors and precancerous histopathologic changes in hamster buccal pouch mucosa. An unexpected finding was that among the HSV-1 infected animals, 95% of the ganglia from animals treated with DMBA showed latent HSV-1 virus on explanation culture, whereas only 10% of the ganglia from infected animals that received mineral oil, rather than DMBA, contained latent virus.

Several investigations have recently shown that chlorhexidine (CHX) has antiviral activity, and they have indicated possible clinical use of CHX for the control of intraoral herpes simplex virus (HSV) infection. In the present study, we have evaluated the in vitro and in vivo therapeutic efficacy of CHX against type 1 HSV (HSV-1) infection. CHX moderately, but significantly, inhibited the replication and cytolytic activity of HSV-1 in Vero cell monolayers. When 0.2% CHX was applied topically onto the HSV-1 infected forehead skin of mice, the development of viral lesions and the viral titers in the skin and trigeminal ganglia were also moderately reduced. These data indicate that CHX oral rinse may be beneficial for the control of intraoral HSV-1 infection in certain patients, and warrants further controlled clinical study.

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.

Systemic or topical treatment with E-5-(2-bromovinyl)2'-deoxyuridine (BVDU) showed significant efficacy against orofacial infection with herpes simplex virus type 1 (HSV-1) in hairless mice. The chemotherapeutic response to BVDU was dose-dependent and clearly evident even when the treatment was initiated during the clinical manifestation of HSV-1 infection at 72 hr after inoculation. Early initiation of therapy with BVDU at 3 or 24 hr after inoculation significantly prevented the establishment of latent HSV infection in the trigeminal ganglia of mice, but systemic treatment with BVDU did not influence already established latent HSV-1. The chemotherapeutic efficacy of BVDU was comparable to that of acyclovir in the present animal model.

Several antiviral agents were applied topically or by iontophoresis to hairless mouse skin inoculated with herpes simplex virus type 1 (HSV-1), and the chemotherapeutic effectiveness was evaluated. Topical application of iododeoxyuridine, arabinoside A, and adenine arabinoside monophosphate (ara-AMP) moderately decreased the average lesion score, number of mice with paralysis, and number of mice dying in HSV-1-infected animals. Also, the mean survival time was moderately prolonged by topical application of those antiviral agents. When ara-AMP was applied by cathodal (-) iontophoresis to the HSV-1-infected skin, the average lesion score, number of mice with paralysis, and number of mice dying were greatly decreased. Furthermore, the mean survival time of mice was highly increased by cathodal (-) iontophoresis of ara-AMP. The therapeutic efficacy of ara-AMP iontophoresis was much superior to the topical application of iododeoxyuridine, arabinoside A, and ara-AMP. These data suggest that ara-AMP iontophoresis would be the method of choice for the management of HSV-1 skin lesions in hairless mice.

Acyclovir and vidarabine exerted a less-than-additive effect on the replication of herpes simplex virus type 1 (HSV-1) in green monkey kidney cells. The synthesis of viral DNA was reduced much more (97%) than that of cellular DNA (45%) by combined acyclovir and vidarabine in cell culture. Furthermore, the combined drugs, given topically or systemically, were more effective than the individual drugs in diminishing the development of clinical signs of HSV-1 infection in hairless mice. However, mortality among animals given topical acyclovir plus vidarabine was not significantly lower than that among animals given topical acyclovir only. Systemic acyclovir (50 mg/kg per day) plus vidarabine (100 mg/kg per day), given for five consecutive days starting 24 hr after viral inoculation, significantly reduced the frequency of development of latent HSV-1 infection in the trigeminal ganglia of mice, whereas systemic acyclovir or vidarabine alone did not.

Systemic treatment of mice with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) showed a significant therapeutic efficacy against herpes simplex type 1 virus (HSV-1) encephalitis. With treatment initiated 12 h after viral inoculation and continued for 10 consecutive days, BVDU administered intraperitoneally in daily doses of 100-500 mg/kg increased the 21-day survival rates from 30 to 100% and reduced brain virus titers by 3-4 log10 on day 6 post-infection. Furthermore, at doses of 300-500 mg/kg per day BVDU prevented the establishment of latent virus infection in the trigeminal ganglia following intracerebral HSV-1 inoculation.

The chemotherapeutic efficacy of acyclovir was evaluated by observing the potential of topical acyclovir to reduce the severity of herpes viral lesions and to control the multiplication of this virus in the experimentally induced primary cutaneous infection of guinea pigs. Topical acyclovir showed a substantially high therapeutic efficacy when treatment was initiated after the development of clinically overt skin lesions. The therapeutic response was dose dependent and clearly evident even when the treatment was initiated on day 2 after inoculation. Our results indicate that topical acyclovir treatment improved the cutaneous herpes simplex virus type 1 (HSV-1) infectious process by inhibiting multiplication of HSV-1 in the skin of guinea pigs.