Cutaneous Herpes Simplex Virus Infection Research Articles

Comparison of n-docosanol cream (LIDAKOL ™) with acyclovir ointment (Zovirax ™) in the inhibition of cutaneous herpes simplex virus (HSV) infections in two guinea pig model systems : J.F. Marcelletti, R.R. McFadden, M.H. Khalil, L.E. Pope, R.C. Davis, L.R. Katz, and D.H. Katz. LIDAK Pharmaceuticals, 11077 N. Torrey Pines Road, La Jolla, CA 92037

Comparison of n-docosanol cream (LIDAKOL ™) with acyclovir ointment (Zovirax ™) in the inhibition of cutaneous herpes simplex virus (HSV) infections in two guinea pig model systems : J.F. Marcelletti, R.R. McFadden, M.H. Khalil, L.E. Pope, R.C. Davis, L.R. Katz, and D.H. Katz. LIDAK Pharmaceuticals, 11077 N. Torrey Pines Road, La Jolla, CA 92037

Treatment of acyclovir-unresponsive cutaneous herpes simplex virus infection with topically applied SP-303

The naturally occurring polyphenolic biopolymer SP-303 has in vitro activity against both HSV-1 and HSV-2, including strains that are resistant to acyclovir. Nine AIDS patients with acyclovir-unresponsive mucocutaneous herpes simplex virus infection were treated with thrice daily topical SP-303T ointment in an open-label pilot study. Although a transient decrease in lesion size was observed in 4 patients during study drug therapy, and 3 patients sustained a quantitative decrease in virus burden, neither complete healing nor cessation of virus shedding occurred in any patient. Seven patients complained of pain or burning upon application of the study ointment, causing 1 patient to terminate the study. In summary, application of SP-303T ointment effected no significant improvement in the clinical course of 9 AIDS patients with acyclovir-unresponsive HSV infection.

Control of Acute Cutaneous Herpes Simplex Virus Infection: T Cell-Mediated Viral Clearance Is Dependent upon Interferon-γ (IFN-γ)

It is well established that T lymphocytes play a critical role in the control and clearance of herpes simplex virus (HSV) infections. However, the role of the CD4 + and CD8 + T cell subsets in the recovery process has not been clearly elucidated. Cutaneous HSV infection of the footpad tissue of C57BL/6 (B6) mice provides a model to determine the relative contribution of each T cell subset during the important early phase of the response to infection. In this study, we observed that the elimination of mature peripheral T lymphocytes by depletion in vivo with a combination of CD4- and CD8-specific monoclonal antibodies prevented recovery from acute infection in this model. However, mice depleted of either the CD4 + or CD8 + subpopulation alone recovered completely, with only a slight delay in the total clearance of infectious virus, Adoptive transfer studies revealed that lymph node cells from donor mice selectively depleted of either CD4 + or CD8 + T cell subset in vivo, or from normal donors selectively depleted in vitro, were able to mediate recovery. As CD4-depleted mice fail to generate a CD8 + T cell-mediated cytolytic T lymphocyte (CTL) response, this suggested that the control of cutaneous HSV infections may be mediated by a cytokine-dependent mechanism common to both the CD4 + and CD8 + T cell subpopulations. It was subsequently found that the neutralization of IFN-γ in vivo diminished the ability of mice to clear infectious HSV from the skin, and treatment with anti-IFN-γ in vivo ablated the ability of transferred T cells to mediate recovery. These studies suggested that IFN-γ-mediated mechanisms play a critical role in the control of and recovery from acute cutaneous HSV infection.

Stress-induced reactivation of latent herpes simplex virus infection in rat lumbar dorsal root ganglia

Clinical reports suggest that stress precipitates recurrent cutaneous Herpes simplex virus (HSV) infection, presumably by reactivating latent infection in sensory ganglia with subsequent centrifugal axonal spread to the skin. As an initial test of this hypothesis, rats with latent HSV, type-1, (HSV-1) infection in lumbar dorsal root ganglia (DRG) were exposed to a well-characterized acute stressor that produced gastric ulcers (U) and elevated plasma corticosterone (CS) concentrations. Stress-induced reactivation of latent HSV infection was suggested by the earlier appearance of cytopathic effect (CPE) in human foreskin fibroblast monolayers co-cultivated with ganglia from stressed rats than from nonstressed ones (4.5 ± 0.2 and 6.4 ± 0.4 [mean ± SEM] days respectively; p<0.001). No CPE was detected in monolayers co-cultivated with ganglia from non-infected rats. These initial results suggest that acute stress reactivates latent HSV-1 ganglionic infection.

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.

A Study of Indirect Immunofluorescence Staining in the Diagnosis of Cutaneous Herpes Simplex Virus Infection

A Study of Indirect Immunofluorescence Staining in the Diagnosis of Cutaneous Herpes Simplex Virus Infection

Synergistic topical therapy by acyclovir and A1110U for herpes simplex virus induced zosteriform rash in mice

Combination therapy with A1110U, an inactivator of the herpes simplex virus (HSV) and the varicella zoster virus ribonucleotide reductase, and acyclovir (ACV) was evaluated for treatment of cutaneous herpetic disease in athymic mice infected on the dorsum. In this model, infection with HSV produces a ‘zosteriform-like’ rash that is first visible on day 3 or 4 post-infection (p.i.) and eventually extends from the anterior mid-line to the dorsal mid-line of the affected flank. In untreated mice, the infection is fatal at about day 7 p.i. presumably due to central nervous system involvement. Topical treatment of infections induced by either wild-type (wt) HSV-1 or wt HSV-2 with 3% A1110U in combination with 5% ACV resulted in synergistic ( P<0.01) reductions in lesion scores. Therapy was also synergistic in mice infected with an ACV-resistant thymidine kinase-deficient mutant and an ACV-resistant TK-altered mutant HSV-1 isolate. Combination therapy was very effective in reducing lesion scores of mice infected with an ACV-resistant HSV-1 DNA polymerase mutant, but did not result in statistically significant synergy ( P = 0.07) because of the enhanced efficacy of A1110U alone against this virus. These results provide encouragement that the combination of A1110U and ACV may offer an effective therapy for topical treatment of cutaneous HSV infections in humans.

Topical treatment of cutaneous herpes simplex virus infections

Topical antiviral chemotherapy has a number of potential advantages over systemic drug delivery for the treatment of cutaneous herpes simplex virus infections, including convenience; higher target tissue drug levels and greater efficacy; and specific targeting of the drug to the site of infection, with reduced cost and reduced exposure of the remainder of the body to drug side effects. Realization of these possibilities has been slow in part because of the paucity of 'active' topical drug formulations with effective penetration-enhancing agents and a technical barrier-our failure as yet to measure drug levels in the epidermis, which could guide formulation development. Recent success with a topical treatment for herpes simplex labialis should stimulate continued laboratory and clinical research in this field.

Cutaneous herpes simplex infections.

To review the clinical features and natural history of cutaneous herpes simplex infections associated with genital herpes. A retrospective case note study of all patients presenting to James Pringle House with this condition between 1983-1987. 123 patients were identified. The commonest sites involved were the buttocks 64/186 (34%), suprapubic area 28/186 (15%) and thigh 14/186 (7.5%). Thirty five of the 123 (28%) patients had more than one anatomical site involved. Genital and extragenital recurrences occurred with similar frequency. Extragenital cutaneous herpes simplex is not uncommon. Lesions may occur virtually anywhere on the body. HSV should always be considered in the differential diagnosis of vesiculating skin lesions.

Rapid Detection of Cutaneous Herpes Simplex Virus Infection with the Polymerase Chain Reaction

A simple and specific method for detecting herpes simplex virus infection in routinely processed paraffin-embedded biopsy specimens is described. DNA is extracted from paraffin blocks, and subjected to DNA amplification with the polymerase chain reaction. After 40 rounds, an amplified band can be detected after agarose gel electrophoresis and ethidium bromide staining. This band is specific for herpes simplex virus, because tissues infected with related viruses do not give this amplified band. We have been able to detect viral DNA in small punch skin biopsies with this procedure, which can take as little as 6 h.

Preclinical studies of iododeoxuridine in dimethyl sulfoxide for the topical treatment of cutaneous herpes simplex virus infections

The topical use of iododeoxyuridine (IDU) in dimethyl sulfoxide (DMSO) for the treatment of cutaneous herpes simplex virus (HSV) infections has been advocated for over 20 years, but the clinical efficacy of this combination remains controversial. The following studies were undertaken to understand better how variable formulations of IDU in DMSO and different rates of percutaneous drug delivery affect clinical efficacy. The flux of IDU from DMSO through excised guinea pig skin was measured in Franz diffusion cells, with varying experimental conditions and formulations of IDU, DMSO and water. Contrary to predictions derived from Fick's law, the flux of IDU did not continue to increase with increasing drug concentration beyond 20% IDU. Higher rates of drug flux were measured when the in vitro experimental conditions more closely replicated those of a skin surface in vivo, that is with the receiver solution at 37°C and skin exposed to ambient conditions. Three IDU-DMSO formulations tested in vitro were used to treat an experimental dorsal cutaneous HSV infection of guinea pigs. The flux values determined at 37°C in the open diffusion cells showed better correlation with treatment efficacy. The results of these experiments may explain in part why very high concentrations of IDU in DMSo may not necessarily be more clinically effective beyond an optimal drug concentration and why results with different IDU-DMSO formulations have been variable.

Therapeutic effect of pyrophosphate analogues on cutaneous herpes simplex virus type 1 infection in guinea pigs

We investigated the influence of disodium phosphonic formate (PFA-Na 2) and trisodium thiophosphonic formate (TPFA-Na 3), in comparison with acyclovir (Zovirax®) and trisodium phosphonic formate (PFA-Na 3) (Triapten®) ointment, on the course of primary cutaneous herpes simplex virus infection in a guinea pig skin model. PFA-Na 2 at 3.0%, TPFA-Na 3 at 0.5% and PFA-Na 3 at 0.5% as well as Triapten ointment (2.0% PFA-Na 3) completely inhibited virus infection. Zovirax cream (5.0% acyclovir), applied five times (15 min., 4, 20, 24, and 28 h) after virus inoculation did not prevent virus infection. Similarly, application of Zovirax cream 5 times daily for 5 days did not prevent a vesicle formation following cutaneous herpes simplex virus infection of the guinea pig.

Measurement of the Stratum Corneum Drug Reservoir to Predict the Therapeutic Efficacy of Topical Iododeoxyuridine for Herpes Simplex Virus Infection

A rapid, in vivo measurement of the penetration of antiviral compounds into the skin would improve our ability to predict the therapeutic efficacy of topical treatments for herpes simplex virus (HSV) infection. We have studied the concentration of iododeoxyuridine (IDU) in the stratum corneum of guinea pig skin by tape stripping at different time points after single and multiple topical doses of the drug. These results were correlated with the efficacy of topical IDU against an experimental cutaneous HSV infection. Ten adhesive tape strippings were performed on depilated guinea pig dorsum in vivo at serial intervals after a single topical dose of [3H]IDU. Iododeoxyuridine levels in the stratum corneum peaked at 1-3 h (67-70 mg/g of tissue) and then gradually declined over the next 3-24 h. We hypothesized that the peak IDU stratum corneum concentration would correlate with therapeutic efficacy. Accordingly, we determined the quantity of IDU in guinea pig stratum corneum 2 h after a topical application of seven different concentrations of IDU in dimethylsulfoxide (DMSO) and examined the in vivo efficacy of these formulations in an experimental dorsal cutaneous HSV-1 infection in guinea pigs. The results showed an excellent correlation between the quantity of IDU in the stratum corneum and reduction in lesion severity (r = 0.95-0.97). Fifteen percent IDU in DMSO provided the highest therapeutic efficacy (90-94%). We also studied the relationship between the clinical efficacy of different dosing frequencies and the amount of IDU in the stratum corneum. Serial IDU stratum corneum concentrations were measured over 24 h following 1, 2, 3, or 4 applications per day of 1, 3, and 15% IDU in DMSO treatments and parallel efficacy studies of the different regimens were conducted in the animal model. Within each dosing frequency, the cumulative amount of drug in the stratum corneum correlated with the strength of the test formulation and with efficacy in the animal model. For each of the three formulations, increasing the number of daily doses from one up to three led to progressive increases in cumulative stratum corneum IDU levels and clinical efficacy. An increase in the number of daily applications to four had little effect on drug efficacy and was associated with a plateau in stratum corneum IDU levels. Stratum corneum IDU concentrations were rapid and easy to determine and correlated well with clinical events.(ABSTRACT TRUNCATED AT 400 WORDS)

Acyclovir resistance in a patient with chronic mucocutaneous herpes simplex infection

Chronic cutaneous herpes simplex virus infection is described in a 68-year-old man who was immunocompromised because of chronic lymphocytic leukemia. The herpes infection was not amenable to therapy with acyclovir. Clinical isolates of herpes simplex virus were assessed for viral thymidine kinase activity, which was markedly decreased in two isolates. By the method of viral plaque autoradiography, these isolates were determined to be composed primarily of mutant thymidine kinase-negative herpes simplex virus mixed with occasional standard thymidine kinase-positive herpes simplex virus. Viral plaque autoradiography permitted the quantitation of proportions of thymidine kinase-negative and thymidine kinase-positive herpes simplex virus in the mixed virus populations. The chronic cutaneous infection persisted, unlike other reported infections by thymidine kinase-negative herpes simplex virus.

Reactivation of latent herpes simplex virus infection by ultraviolet light: A human model

Infection with herpes simplex virus often results in a latent infection of local sensory ganglia and a disease characterized by periodic viral reactivation and mucocutaneous lesions. The factors that trigger reactivation in humans are still poorly defined. In our study, five patients with documented histories of recurrent herpes simplex virus infection on the buttocks or sacrum were exposed to three times their minimal erythema dose of ultraviolet light. Site-specific cutaneous herpes simplex virus infection occurred at 4.4 +/- 0.4 days after exposure to ultraviolet light in 8 of 13 attempts at reactivation. We conclude that ultraviolet light can reactivate herpes simplex virus under experimentally defined conditions. This model in humans should prove useful in evaluating the pathophysiology and prevention of viral reactivation.

Langerhans Cell—and T-Lymphocyte Functions in Patients With Atopic Dermatitis With Disseminated Cutaneous Herpes Simplex Virus Infection

We studied whether Langerhans cell (LC)- and T-lymphocyte functions of atopic dermatitis (AD) patients are impaired. Our study groups consisted of 6 patients with AD with previous disseminated herpes simplex virus infection (AD + HSV), 8 patients with ordinary AD, and 5 healthy subjects. Suction blisters were performed on abdominal skin and LC isolated on the basis of their attachment to IgG-coated erythrocyte monolayers. Antigen-presenting function of purified LC was studied by measuring the proliferation of HSV-stimulated T cells. Langerhans cells were also used to stimulate T cells in autologous mixed cell reaction (AMCR). In addition, the production of epidermal cell thymocyte-activating factor (ETAF) by crude epidermal cells was measured. The HSV-induced T-cell proliferation in AD + HSV and AD patients was comparable with that of controls. The AMCR responses of patients with AD + HSV and AD were clearly diminished when compared with healthy controls. Patients with AD also produced significantly less ETAF than controls. Our results suggest that HSV antigen-presenting function of LC from patients with AD + HSV seems to be intact. Defective AMCR may reflect an abnormality in autoregulation and generation of effector cells and this together with decreased ETAF production may have pathogenetic significance in AD.

Role of epidermal Langerhans cells in resistance to herpes simplex virus infection.

To investigate the role of epidermal Langerhans cells (LC) in resistance to herpes simplex virus (HSV) infection, nonadherent spleen cells taken from BALB/c mice immunized with HSV were cultured with syngeneic epidermal cells (EC) and ultraviolet light-inactivated HSV antigen. After five days of culture, T cell-dependent proliferative response was determined by 3H-thymidine incorporation. Treatment of EC with anti-Iad monoclonal antibody plus complement before cultivation prevented this proliferation, which suggested that LC induced stimulation of immune T cells. When these stimulated spleen cells were transferred to intracutaneously infected nude mice, the virus titer in the skin was reduced markedly and the formation of zosteriform skin lesions was completely inhibited. On the other hand, transfer of unstimulated cells, which were cultured with HSV antigen only or with HSV antigen and EC treated with anti-Iad monoclonal antibody plus complement, resulted in delayed viral clearance and development of the lesions. These results indicate that LC are of importance as accessory cells in the control of cutaneous HSV infection. Furthermore, Lyt 1+ T cells in the stimulated population were shown to have greater protective activity than Lyt 2+ T cells.

Treatment of Eczema Herpeticum With Systemic Acyclovir

Eczema herpeticum, a form of disseminated cutaneous herpes simplex infection, is a potentially life-threatening illness.¹Herpes simplex virus may disseminate either cutaneously or systemically in patients with preexisting cutaneous disease, including Darier's disease, pemphigus vulgaris, ichthyosis vulgaris, mycosis fungoides, and most commonly, atopic dermatitis.^1,2 The initial manifest herpes simplex virus infection may be from a primary exposure or after reactivation of a latent infection. The latter infection, occurring in patients with certain preexisting dermatoses, may manifest initially with a localized cluster of lesions which, with time, may disseminate over a larger skin surface area. The manifestation may be confused with an exacerbation of the underlying skin disease until the characteristic vesicles are noted. When associated with atopic dermatitis, the most intense viral dissemination is located in the areas of dermatitis, but normal appearing skin may ultimately be involved. Crops of new vesicles continue to erupt for two to

Effect of azone and propylene glycol on penetration of trifluorothymidine through skin and efficacy of different topical formulations against cutaneous herpes simplex virus infections in guinea pigs

Tropical formulations of 5-trifluoromethyl-2'-deoxyuridine (TFT) containing different concentrations of TFT, Azone (Nelson Research and Development, Irvine, Calif.), and propylene glycol were evaluated for their potential efficacy in the treatment of cutaneous herpes simplex virus infections by in vitro studies of TFT penetration through skin and in vivo studies of therapeutic activity against herpes simplex virus type 1 infections in the dorsal cutaneous guinea pig model. Azone dramatically increased TFT penetration through human and guinea pig skin. Unexpectedly, high concentrations of propylene glycol were also associated with increased penetration. Studies in the guinea pig model revealed increased efficacy with Azone-propylene glycol-containing formulations, consistent with the in vitro drug diffusion results. A formulation containing 1% TFT, 5% Azone, and 80% propylene glycol decreased lesion area, in comparison to the drug vehicle control, more effectively than 5% acyclovir in polyethylene glycol (reduction of 70 versus 46%, P = 0.03). These studies demonstrate the value of penetration-enhancing agents and the need for careful preclinical evaluations in the development of topical antiviral agents.

Cutaneous herpes simplex virus infection of the guinea pig: lack of resistance to acyclovir and phosphonoformic acid after topical treatment

Guinea pigs were infected cutaneously with HSV1 and treated topically with acyclovir or phosphonoformic acid (0.1% to 0.5% solution), or with a combination of both. The therapy was clinically effective and the virus content in the skin diminished. Virus harvests from skin areas in no case showed increased drug resistance, as tested by plaque reduction.