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Biomedical subjects

L R Stanberry

Publications and source records attributed to L R Stanberry.

At least 73 records · Page 4Linked to original sources
PubMed1993

Evaluation of HPMPC therapy for primary and recurrent genital herpes in mice and guinea pigs.

The nucleoside analogue (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) inhibited the replication of herpes simplex virus (HSV) types 1 and 2 in tissue culture cells at about 1.0 micrograms/ml, whereas Acyclovir (ACV) had an EC50 of about 0.10-0.50 micrograms/ml. The purpose of these studies was to evaluate the efficacy of topically applied HPMPC in animal models of primary and recurrent genital HSV-2 infections. Mice treated with 5%, 1% or 0.5% HPMPC three times daily, beginning 6 or 24 h after virus inoculation had reduced vaginal viral replication regardless of time of initiation of therapy. ACV at 5% also reduced vaginal viral replication, but not as effectively as HPMPC. In primary infection of guinea pigs, therapy with 5% or 1% HPMPC beginning at 24 h but not 72 h significantly altered lesion development. However, 5% HPMPC was highly toxic to guinea pigs. Vaginal viral replication was reduced significantly with either 1% or 0.3% HPMPC initiated at 24 h. In these studies, HPMPC was also more efficacious than 5% ACV. Topical treatment with 1% HPMPC did not reduce the incidence or severity of spontaneous or UV-induced recurrent genital lesions. These results indicate that topical therapy with 1%, 0.5% or 0.3% HPMPC was more effective than 5% ACV in the treatment of primary genital HSV-2 infections of guinea pigs and mice and suggest that HPMPC should be considered for topical use in humans.

Acyclovir↗
PubMed1993

Detection of varicella-zoster virus DNA in nasopharyngeal secretions of immune household contacts of varicella.

Persons immune to varicella-zoster virus (VZV) are not at risk for developing clinical infection after exposure to varicella. However, the extent to which they might serve as vectors for the transmission of VZV to others is not known. Information in this regard would be important in establishing hospital infection control policies, especially in relation to the care of immunocompromised hosts. A polymerase chain reaction-based detection system was used to detect the presence of VZV DNA in the nasopharyngeal secretions of household contacts of children with varicella. VZV DNA was identified in 4 of 5 immune adults and 1 susceptible sibling when sampled within 3 days of recognition of a household case of varicella. Further investigations are needed to determine whether this represents a limited window of VZV replication in the nasopharynx of immune persons during which they may serve as vectors of VZV.

Adult↗
PubMed1993

Effect of indomethacin on ultraviolet radiation-induced recurrent herpes simplex virus disease in guinea-pigs.

Exposure to u.v. radiation increases the local level of prostaglandins which may play a role in u.v. radiation-induced herpes simplex virus (HSV) recurrences. We used the guinea-pig model of u.v. radiation-induced recurrent genital HSV-2 disease for examining the effects of indomethacin, a prostaglandin inhibitor, on u.v.-induced recurrences. In the first experiment, performed 100 days after HSV-2 inoculation, treatment with indomethacin for 5 days begun 24 h before u.v.-irradiation decreased the proportion of animals developing HSV disease recurrences from 11/13 (84.6%) to 2/13 (15.4%) (P < 0.001). In the second experiment, performed 135 days after HSV-2 inoculation, treatment with indomethacin for 5 days begun 24 h before u.v.-irradiation decreased the number of animals developing recurrences from 12/21 (57.1%) to 5/21 (23.8%) (P < 0.05). Five days of indomethacin treatment begun 4 h after u.v.-irradiation, however, did not reduce the percentage of animals developing disease recurrences but did decrease the mean number of days with recurrent lesions in animals that developed recurrences. Our data suggest that indomethacin may modify u.v. radiation-induced recurrent lesions by decreasing viral reactivation when given before u.v. radiation exposure or by reducing prostaglandin-induced immunosuppression when given before or after exposure. Future studies are needed for evaluating indomethacin prophylaxis for recurrent HSV disease when prolonged u.v. radiation exposure is anticipated.

Animals↗
PubMed1992

Outcome of herpes simplex virus type 2 infection in guinea pigs.

Factors that influence the outcome of genital herpes simplex virus (HSV) infection were explored in a guinea pig model. The viral inoculum required to establish infection in 50% of animals (ID50) was similar for inbred (strain 2) and outbred (Hartley) guinea pigs. However, the viral inoculum required to produce clinical disease in 50% of the animals (CD50) was 10 times greater for strain 2 compared to Hartley animals. HSV infection of both inbred and outbred animals was more likely to result in death of weanling than adult animals. The duration and severity of genital disease and the magnitude of vaginal viral replication were similar for strain 2 and Hartley animals in both young and adult animals. The lethal dose for 50% of animals (LD50) was 100-fold greater than the CD50 for Hartley animals, but the LD50 and the CD50 were equal in strain 2 guinea pigs. Viral cultures of homogenized neural tissues from infected animals revealed that HSV ascended to the level of the temporal cortex in strain 2 guinea pigs while virus was never recovered above the lumbar spinal cord in Hartley animals. Endogenous peripheral blood mononuclear cell-mediated cytolytic activity against HSV-infected targets was greater prior to HSV inoculation in survivors compared to animals that died. A fatal outcome of genital HSV-2 may relate to the failure to limit CNS viral replication. Death is more common among guinea pigs that have low endogenous HSV-directed natural killer activity, such as occurs among strain 2 and young animals whether inbred or outbred.

Administration, Intravaginal↗
PubMed1992

Capsaicin-sensitive peptidergic neurons are involved in the zosteriform spread of herpes simplex virus infection.

The intraneuronal transport of herpes simplex virus (HSV) is an essential component in disease pathogenesis. Capsaicin, a neuropharmacologic agent lacking direct antiviral activity, has been shown to protect animals against HSV-induced disease. It has been hypothesized that capsaicin acts by interfering with the intraneuronal transport of virus. Since animal models have been useful in studying the spread of virus, we used two guinea pig models of zosteriform herpes to examine the effect of capsaicin on HSV spread. Capsaicin was subcutaneously administered to Hartley guinea pigs prior to intravaginal or cutaneous HSV-2 inoculation. Treatment did not prevent the development of herpetic vesicles at the site of inoculation but significantly reduced the zosteriform spread of lesions in male and female animals. Further, after recovery from primary infection, capsaicin-treated male guinea pigs were observed to have fewer days with recurrent herpetic lesions. These results suggest that capsaicin-sensitive nerve fibers play a role in the pathogenesis of primary and recurrent HSV infections. Capsaicin appears to reduce the severity of cutaneous HSV infections by interfering with the spread of virus.

Animals↗
PubMed1992

Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes.

Herpes simplex virus (HSV)-coded thymidine kinase (TK) is important in efficient reactivation of latent infection. These studies were designed to investigate whether treatment of latently infected animals with a TK inhibitor altered the natural history of recurrent HSV disease. 9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) is a potent and selective nonsubstrate inhibitor of HSV TK which can suppress or delay reactivation of HSV-1 from latently infected cells in vitro without affecting viral replication. In an initial study, six female Hartley guinea pigs were treated with L-653,180 in their diet (25 mg/30 g of food) and water (300 mg/liter) for 7 days. Blood, urine, kidney, liver, spinal cord, and cerebral cortex specimens were collected. L-653,180 was detected in all specimens at concentrations which, although low, were higher than the in vitro 50% inhibitory concentration of the drug against HSV TK. In the second study, 20 female Hartley guinea pigs were randomized into two groups following recovery from primary genital HSV-2 infection. One group received L-653,180 in diet and water for 4 weeks beginning 21 days postinoculation. Animals were examined daily for recurrent lesions for 10 weeks. Treated animals experienced fewer recurrences during the treatment period but the results were not significantly different from results with controls. During the first 2-week posttreatment period, L-653,180-treated animals had significantly fewer recurrences than control animals (P = 0.02). Over the entire 10-week observation period, treated animals experienced fewer recurrences (P = 0.06). These results suggest that inhibitors of viral TK may be useful in limiting reactivation of latent virus and thus recurrent infections. In these experiments, the amount of drug that could be administered to the animals was limited by its poor solubility. Further studies with more potent and soluble inhibitors of HSV TK appear to be warranted.

Animals↗
PubMed1991

Cell-mediated immunologic responses and recurrent genital herpes in the guinea pig. Effects of glycoprotein immunotherapy.

The specific immune alterations associated with HSV recurrences are ill defined although it appears that alterations in cell-mediated immune mechanisms are more likely associated with recurrent disease than humoral immunity. Immunization with HSV glycoproteins B and D (gBgD) after primary HSV infection has reportedly reduced the frequency of recurrences but the mechanisms remain unidentified. We therefore evaluated the effects of immunization with cloned gBgD on selected cell-mediated immune responses and their relationship to recurrent disease by using the guinea pig model of genital HSV-2 infection. In two experiments, immunization with gBgD + CFA on days 21 and 42 after HSV-2 inoculation significantly decreased the number of subsequent recurrent lesion days observed whereas CFA alone had no effect. Immunization with gBgD + CFA increased the lymphoproliferative and in vitro IL-2 response to gBgD more than to whole HSV-2 Ag preparations. Peak responses were observed 2 wk after the second immunization. The HSV-specific cytolytic response was also persistently increased beginning 1 wk after the first immunization. Analysis including both untreated and gBgD-immunized animals revealed that recurrent lesion days were inversely correlated to the IL-2 response to whole HSV-2 Ag (p less than 0.0001), the IL-2 response to gBgD (p = 0.0004), and the HSV-specific cytolytic response (p = 0.005 and 0.003 in two experiments, respectively). When the untreated group was analyzed separately, only the IL-2 response to whole HSV-2 Ag correlated to recurrences (p = 0.007). HSV glycoprotein immunization may increase IL-2 or other cytokines secreted by HSV-sensitized T cells increasing critical immune responses, such as NK- or lymphokine-activated killer-mediated cytolysis, that could eliminate the reactivated virus before the development of clinically apparent lesions.

Animals↗
PubMed1991

Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs.

We have recently reported that latently HSV-2-infected guinea pigs exhibit a three- to four-fold increase in recurrent lesions after exposure to ultraviolet radiation (UV), allowing rapid evaluation of antiviral drugs in treating recurrent HSV disease. In this report we examine the effect of alpha interferon (IFN-alpha), interleukin-2 (IL-2), and a cytokine inducer (R-837) on UV-induced recurrent genital herpes. We have previously shown that topical R-837 is a biologic response modifier with no in vitro anti-HSV activity, but with potent anti-HSV activity in vivo due to cytokine induction and enhancement of cell-mediated immune responses. Three-day regimens of intravaginal R-837, or five-day intraperitoneal (i.p.) administration of IFN-alpha or of IL-2 each significantly reduced recurrent genital HSV-2 disease that occurred within 7 days of UV exposure, suggesting that cytokines or cytokine inducers may be useful in the treatment of recurrent HSV disease. This model using ultraviolet radiation to induce recurrent herpes simplex virus infection proved useful in the evaluation of immunoactive agents as putative antiviral drugs.

Adjuvants, Immunologic↗
PubMed1991

Drug testing for activity against varicella-zoster virus in hairless guinea pigs.

Inoculation of congenitally hairless guinea pigs with varicella-zoster virus (VZV) (Oka strain) results in a self-limited exanthematous infection analogous to varicella in children. Administration of acyclovir or 6-methoxypurine arabinoside modified the course of infection. This model should facilitate pre-clinical testing of putative anti-VZV agents.

Acyclovir↗
PubMed1991

Varicella in hairless guinea pigs.

A high proportion of depilated newborn or euthymic congenitally hairless adult guinea pigs develop an erythematous papular exanthem during infection with varicella-zoster virus (VZV) previously cultivated in guinea pig cell culture. Virus has been demonstrated in tissues during varicella using polymerase chain reaction amplification and nucleic acid hybridization methods. The frequency of exanthem expression can be reduced by the prophylactic administration of VZV convalescent-phase guinea pig serum. This model should prove useful for further study of VZV pathogenesis as well as for testing putative antiviral compounds.

Animals↗
PubMed1990

Recurrent genital herpes in the guinea pig augmented by ultraviolet irradiation: effects of treatment with acyclovir.

The guinea pig model of genital herpes simplex virus infection has proven useful in the evaluation of antiviral drugs. We have recently demonstrated that recurrent herpetic infections can be induced in latently infected guinea pigs by ultraviolet irradiation. In this report we have examined the effect of acyclovir on ultraviolet radiation-induced recurrent genital herpes. Prophylactic topical acyclovir decreased the severity but not the incidence of ultraviolet radiation-induced recurrences while intraperitoneal acyclovir initiated before ultraviolet irradiation reduced both the incidence and severity of induced recurrences. When treatment was begun after ultraviolet exposure, neither topical nor intraperitoneal acyclovir were effective in reducing the incidence or severity of induced recurrent disease. The effectiveness of acyclovir in the control of induced recurrent genital infections in the guinea pig is similar to what has been observed in human trials. This model of ultraviolet radiation-induced recurrent herpes simplex virus infection should prove useful in the evaluation on new putative antiviral drugs.

Acyclovir↗
PubMed1990

Capsaicin interferes with the centrifugal spread of virus in primary and recurrent genital herpes simplex virus infections.

The neural spread of herpes simplex virus (HSV) via sensory nerves is an essential component of disease pathogenesis. Capsaicin, a specific toxin for sensory C-type fibers, interferes with neuronal function including axonal transport. Capsaicin treatment of guinea pigs before intravaginal HSV inoculation did not prevent ganglionic infection but ameliorated cutaneous herpetic disease, suggesting that anterograde but not retrograde virus spread involved a capsaicin-sensitive process. Similarly, treatment of latently infected animals reduced both spontaneous and ultraviolet radiation-induced herpetic recurrences, suggesting that capsaicin interfered with the anterograde spread of reactivated virus. These results suggest that the centrifugal spread of virus may involve either different pathways or mechanisms than are involved in centripetal HSV spread. The use of selective neuropharmacologic agents such as capsaicin may prove useful in further defining the pathophysiology of HSV disease.

Animals↗
PubMed1990

Detection of asymptomatic initial herpes simplex virus (HSV) infections in animals immunized with subunit HSV glycoprotein vaccines.

The evaluation of herpes simplex virus (HSV) vaccine efficacy will require methods to detect asymptomatic acquisition of HSV infection and to assess the risk of recurrences in these patients. HSV-infected vaccinees should develop antibodies to HSV polypeptides not included in subunit vaccines. Sera from 57 HSV glycoprotein-vaccinated guinea pigs that had asymptomatic initial infections after genital HSV type 2 challenge were collected after vaccination but before HSV challenge and again 30 days after HSV challenge to determine the antibody response to HSV polypeptides. Antibodies to nonvaccine HSV polypeptides were detected in sera collected after viral challenge from 32 (56%) of these 57 animals. Twenty-six (81%) of the 32 animals with detectable antibody developed recurrent disease; however, recurrences also developed in 11 (44%) of the remaining 25 that did not show detectable antibody to nonvaccine HSV polypeptides. The magnitude of vaginal viral shedding during the initial disease period following challenge was significantly lower in animals that did not develop antibody to nonvaccine polypeptides compared with those that did develop antibody (area under the viral shedding curve, 5.2 +/- 3.2 versus 18.1 +/- 5.8; P less than 0.0001) . These data suggest that detection of antibody to nonvaccine HSV polypeptides will identify the majority (70%) of initially asymptomatic vaccinees that develop recurrent disease but that latency can be established even with markedly reduced levels of viral replication that did not induce a detectable antibody response.

Animals↗
PubMed1989

Animal model of ultraviolet-radiation-induced recurrent herpes simplex virus infection.

The development of a model of induced recurrent herpes simplex virus disease would facilitate studies of the mechanism(s) responsible for reactivation of latent virus. The guinea pig model of genital herpes is characterized by a self-limited primary infection, the establishment of a latent infection in sensory ganglia, and the subsequent development of spontaneous recurrent genital infections. This study reports that exposure of latently infected female guinea pigs to ultraviolet radiation results in the induction of recurrent genital herpes simplex virus infections in approximately 60% of animals. Furthermore, there was a dose-response relationship between ultraviolet irradiation and ability to induce recurrent disease. This model should prove useful in further investigations of the pathophysiology of herpes simplex infections.

Animals↗
PubMed1989

Preinfection prophylaxis with herpes simplex virus glycoprotein immunogens: factors influencing efficacy.

Using a guinea-pig model of genital herpes simplex virus (HSV) infection we explored the protection afforded by preinfection immunization with HSV glycoproteins. Glycoprotein immunogens prepared by recombinant DNA technology were found to be as effective as immunogens purified from HSV-infected cell cultures. Immunized animals developed less severe primary disease and also experienced less frequent recurrent infections. Protection was influenced by both adjuvant and route of administration. These studies suggest that recombinant HSV glycoproteins may be effective immunogens for human clinical trials, but that the development of an effective vaccine will require identification of new potent adjuvants that are safe for human use.

Adjuvants, Immunologic↗
PubMed1988

Herpes simplex virus glycoprotein treatment of recurrent genital herpes reduces cervicovaginal virus shedding in guinea pigs.

Treatment of previously infected guinea pigs with herpes simplex virus (HSV) glycoproteins reduces the frequency and severity of subsequent genital recurrences. An effective vaccine should also reduce episodes of viral shedding. In this study, HSV glycoproteins B and D treatment of animals experiencing recurrent genital herpes reduced the frequency of both clinical recurrences and cervicovaginal viral shedding. When virus was shed, however, the peak viral titer and duration of shedding was unaltered.

Animals↗