Richard J. Klein

Latent Herpes Simplex Virus Infections in Sensory Ganglia of Hairless Mice Prevented by Acycloguanosine

Acycloguanosine (ACG) was able to prevent the fatal outcome of herpes simplex virus-induced skin infections of the lumbosacral or orofacila area in hairless mice. Topical ACG treatment was more effective than systemic treatment in preventing the evolution of skin lesions. Acute ganglionic infections in the trigeminal ganglia were prevented by ACG, and latent ganglionic infections did not become established when the ACG treatment was initiated 3 h after infection. Serum antibody titers were, on the average, eight times higher in mice which developed latent ganglionic infections after ACG treatment than in mice without evidence of herpes simplex virus latency in ganglia. Reinoculation of ACG-treated mice at a site different from that of the primary inoculation did not lead to the establishment of a second latent infection with the homologous virus type when a latent infection was already present. In mice without evidence of latent infection after the primary inoculation, a latent infection at the site of reinoculation became established in 25% of the animals.

Phosphonoacetic Acid-Resistant Herpes Simplex Virus Infection in Hairless Mice

Phosphonoacetic acid (PAA)-resistant type 1 herpes simplex virus population was isolated by repeated passage of the virus in the presence of this inhibitor. Hairless mice infected percutaneously with the inhibitor-resistant or the parental inhibitor-susceptible virus were treated intraperitoneally with PAA and 9-β-d-arabinofuranosyl-adenine by using several different dosage schedules. Whereas 9-β-d-arabinofuranosyl-adenine was effective both in the PAA-susceptible and PAA-resistant herpes simplex virus-induced skin infection, PAA suppressed only the infection induced by the parental PAA-susceptible virus.

Treatment of recurrent genital herpes with topical alpha interferon gel combined with nonoxynol 9

A double-blind, placebo-controlled study was done to evaluate the efficacy of an alpha interferon preparation in 128 patients with recurrent genital herpes. The preparation containing 10(5) or 10(7) U alpha interferon with nonoxynol 9 in a cream base (Exovir-HZ) was applied three times daily for 5 days. The treatment did not cause any adverse reactions. Patients treated with either interferon concentration became negative for viral culture at a faster rate than placebo recipients. The end of new lesion formation, scabbing, and the healing of lesions were all superior in patients treated with 10(5) U to those treated with 10(7) U interferon. End of new lesion formation and scabbing were also statistically different in patients treated with 10(7) U from those patients treated with placebo. Results suggest that topical interferon might be useful in relieving symptoms of severe cases of genital herpes.

Native herpes simplex virus glycoprotein D vaccine: immunogenicity and protection in animal models.

Mice, guinea pigs, and rhesus monkeys were immunized with immunoaffinity-purified native glycoprotein D (gD) derived from herpes simplex virus type 1 (HSV1). The native glycoprotein has evoked significant in vivo responses even at low doses. Thus, mice immunized with doses as low as 1 microgram were significantly protected from the morbidity and mortality of lethal HSV2 challenge and from establishment of latent HSV2 infection. Protection was dose-related and correlated with prechallenge serum neutralizing antibody titres to HSV. Similarly, immunized guinea-pigs demonstrated significant reductions in the frequency, severity and duration of genital lesions induced by HSV2 vaginal challenge. In long term immunogenicity studies, immunized rhesus monkeys exhibited significant serum neutralizing antibody responses to both HSV1 and HSV2. In vitro stimulation of monkey peripheral blood leucocytes with purified gD resulted in a significant cellular proliferative response. The results obtained in these animal models with a gD subunit vaccine provide an appropriate foundation for the initiation of human studies.

Intravenous acyclovir therapy of first episodes of genital herpes: A multicenter double-blind, placebo-controlled trial

PURPOSE A collaborative multicenter double-blind, placebo-controlled trial of intravenous acyclovir treatment of first-episode genital herpes was performed in order to substantiate previous findings on the efficacy and safety of this drug, to evaluate the influence of parenteral therapy on recurrence frequency, and to obtain further data on the natural history of genital herpes. PATIENTS AND METHODS Eighty-two patients with first episodes of genital herpes simplex virus (HSV) infection were randomly assigned in a double-blind fashion to treatment with intravenous acyclovir (5 mg/kg every eight hours) or placebo for five days. Before therapy, all lesions in the genital/perineal area and in extragenital sites were cultured. New lesions appearing in both areas after the onset of therapy were cultured separately. Lesions in all groups were cultured until completely healed. Sera were collected from all patients on entry to the study and on Day 21 to determine presence or absence of antibodies to HSV-1 and HSV-2. Time to healing, time to crusting, time to cessation of viral shedding, and appearance of new lesions during therapy were compared for each treatment group. RESULTS Patients receiving acyclovir experienced a significant reduction in the median duration of pain (4.3 versus 4.8 days, p = 0.019), viral shedding (1.9 versus 8.4 days, p less than 0.001), and time to healing (8.4 versus 11.5 days, p = 0.02) compared with placebo recipients. These differences were largely attributable to the effect of therapy in the subset of patients with primary disease in whom acyclovir reduced the median duration of pain from 10.6 days to 4.2 days, the median duration of viral shedding from 17.1 days to 1.9 days, and the median time to healing from 14.2 days to 8.3 days. The rate of subsequent recurrence of genital herpes was not altered by acyclovir treatment: 24 of 32 acyclovir recipients (75 percent) experienced one or more recurrences during a mean follow-up of 14 months compared with 19 of 27 placebo recipients (70 percent). Among patients experiencing recurrences, the mean number of recurrences per month among acyclovir recipients was 0.25 compared with 0.19 for patients given placebo. CONCLUSION This multicenter trial confirms the efficacy of intravenous acyclovir in the management of first-episode genital herpes, especially in patients with primary infection. However, therapy did not alter the frequency of recurrences.

Experimental skin infection with an Acyclovir resistant herpes simplex virus mutant: Response to antiviral treatment and protection against reinfection

SummarySkin infections induced in hairless mice with an Acyclovir resistant herpes simplex virus (HSV) mutant were not followed by the death of the animals, and the survivors had no evidence of latent infections in their sensory ganglia. However, mutant virus was detected in the ganglia during the acute phase of the infection. Mice inoculated with the mutant were fully protected against the fatal outcome of the infection when subsequently challenged with the relatively pathogenic parental virus. In addition the frequency of latent infections established after challenge was significantly reduced. Phosphonoacetic acid treatment of the primary mutant-induced infection abolished the protection against reinfection with parental virus. Acyclovir treatment of the primary infection with the mutant virus did not affect the protection against reinfection with parental virus. The results indicate that drug-resistant, latency-negative, HSV mutants are a promising starting point for the development of an attenuated HSV vaccine.

Herpes Simplex Virus Skin Infection in Hairless Mice: Treatment with Antiviral Compounds

A hairless mouse-herpes simplex virus skin infection experimental model was used to evaluate the efficacy of the antiviral compounds 9-β-d-arabinofuranosyladenine (ara-A), 5-iodo-2′-deoxyuridine (IUdR), and 6-azauridine (aza-U). Ara-A and IUdR, when administered intraperitoneally by several different dosage schedules, reduced the severity of cutaneous herpetic lesions and the incidence of paralysis and increased significantly the number of survivors. A more rapid healing of the lesions and an increase in the mean survival time also was observed. A delay of 24 to 48 h in the initiation of treatment after the infection was more effective than treatments started at the time of inoculation. Treatment with ara-A was somewhat superior to that with IUdR, but aza-U was totally ineffective. Enhancement of the evolution of the infection was noted after treatment with aza-U.

Latent Herpes Simplex Virus Infections in Sensory Ganglia of Mice After Topical Treatment with Adenine Arabinoside and Adenine Arabinoside Monophosphate

Adenine arabinoside (Ara-A) and Ara-A monosphosphate (Ara-AMP) ointments were able to prevent the fatal outcome of herpes simplex virus (HSV)-induced skin infection of the lumbosacral area in hairless mice. Ara-A and Ara-AMP had no irritating effect on the skin, but in a number of animals a protracted healing time of the skin lesions after the treatment was observed. The compounds conferred only a partial protection against the establishment of latent HSV infection in the spinal root ganglia of the treated animals. The immune response, as judged from levels of HSV-specific neutralizing serum antibody titers, was not impaired by the antiviral treatment.

Effect of acyclovir on latent herpes simplex virus infections in trigeminal ganglia of mice.

The inhibition by acyclovir of the in vitro reactivation of herpes simplex virus from latently infected ganglion explant cultures is dependent on the continuous presence of this drug. Administration of acyclovir subcutaneously, orally, or by continuous perfusion to mice with established latent infections did not eliminate latent virus from the trigeminal ganglia.

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

SummaryHerpes 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.