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Cellular immune responses to Herpes simplex virus type 1 in recurrent herpes labialis: in vitro blastogenesis and cytotoxicity to infected cell line.

Cellular immunity to herpes simplex virus type 1 (HSV-1) in 12 volunteers with recurrent herpes labialis was evaluated by means of two microassays. In the blastogenesis assay, lymphocytes were incubated with tissue culture cells persistently infected with HSV-1. Uninfected cells were used as controls, and a blastogenic index was calculated. The mean blastogenic index (plus or minus SD) for subjects with recurrent herpes labialis was 26.9 (plus or minus 8.3); the mean blastogenic index (plus or minus SD) in control donors with antibody to HSV-1 was 13.4 (plus or minus 7.2). The difference between these values was statistically significant (t equals 4.154; P smaller than 0.001). In the cytotoxicity assay, cells of the same persistently infected line were used as target cells, and release of 51-Cr from these cells or from control cells served as the index of lymphocyte reactivity. Specific immune release attributable to HSV-1 averages 3.7% (plus or minus 1.8%) in subjects with recurrent herpes labialis, compared with 23.1% (plus or minus 9.8%) in controls (t equals 6.135; P smaller than 0.001). These data suggest a dissociation between mechanisms of cellular immunity, with enhanced lymphocyte blastogenesis but decreased cytotoxicity. Recurrent herpes labialis may thus result from subtle cellular immune deficiency involving at least one of the efferent mechanisms.

Adenoma↗

Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group.

BACKGROUND AND OBJECTIVES: Valaciclovir, the L-valine ester prodrug of acyclovir, is much better absorbed than acyclovir and produces acyclovir exposures three to five times those attainable with the parent drug. GOALS: To determine whether the improved bioavailability of valaciclovir and a more convenient, less frequent dose regimen can maintain the clinical efficacy previously demonstrated for acyclovir. STUDY DESIGN: This was an international, multicenter, randomized, double-blind clinical trial comparing 10-day regimens of valaciclovir (1000 mg, twice daily) and acyclovir (200 mg, 5 times daily) in the treatment of 643 otherwise healthy adults (> or = 18 years of age) with first-episode genital herpes. Patients were evaluated clinically and lesions were staged and cultured on days 1, 2, 3, 5, 7, 10, 14, and then twice weekly until healed. Blood for herpes serology tests was obtained on days 1 and 14; hematology and chemistry toxicity screening was done on days 1 and 7. RESULTS: Valaciclovir and acyclovir did not differ significantly in efficacy with respect to duration of viral shedding (hazard ratio, 1.00; 95% confidence interval [CI], 0.84-1.18), time to healing (hazard ratio, 1.08; 95% CI, 0.92-1.27), duration of pain (hazard ratio, 1.0; 95% CI, 0.85-1.18), and time to loss of all symptoms (hazard ratio, 1.02; 95% CI, 0.85-1.22). Patients with primary genital herpes (no preexisting antibody to either herpes simplex virus type at enrollment with seroconversion at day 14) had longer times to healing and longer duration of viral shedding and pain than patients with nonprimary first genital episodes. Adverse experiences were generally infrequent and mild and were comparable in the two treatment groups. CONCLUSIONS: Twice-daily valaciclovir proved as effective and well tolerated in the treatment of first-episode genital herpes as five-times-daily acyclovir. Valaciclovir provides a useful alternative to acyclovir with the advantage of a more convenient dosing regimen and the potential for improved compliance.

Acyclovir↗

Herpes simplex virus type 1 is the prevailing cause of genital herpes in the Tel Aviv area, Israel.

BACKGROUND AND GOAL: The changing epidemiology of genital herpes with the increasing importance of herpes simplex virus (HSV) type 1 prompted a study on the relative prevalence of HSV-1 and HSV-2 among cases of genital herpes in the Tel Aviv area, Israel. STUDY DESIGN: A retrospective laboratory-based study of positive genital and nongenital herpes cultures performed at the Beilinson Medical Center between 1993 and 2002. Data regarding the number of isolates of each type and the age and sex of patients with genital lesions were retrieved from the database. Cultures were performed using Vero cells, and positive results were confirmed and typed by immunofluorescence. RESULTS: A total of 285 positive genital cultures and 659 positive nongenital cultures were recorded. HSV-1 was identified in 189 (66.3%) of the positive genital specimens and in 656 (99.55%) of the nongenital specimens. HSV-1 was isolated in 174 of 262 (66.4%) female subjects and 15 of 23 (65.2%) male subjects. The proportion of HSV-1 genital isolates was 72.7% in patients 15 to 24 years of age, 62% in those 25 to 44 years, and 46% in those aged 45 years or older. Overall, the annual isolation rate of genital HSV-1 has not changed markedly over the years. CONCLUSION: Herpes simplex virus type 1 has clearly been the predominant HSV type isolated from genital specimens in the Tel Aviv area over the last decade.

Adolescent↗

Herpes simplex virus type 1 remains the principal cause of initial anogenital herpes in Edinburgh, Scotland.

GOAL: The goal of this study was to investigate the trends in the prevalence of anogenital herpes caused by herpes simplex virus (HSV) type-1 and HSV-2 among patients attending a sexually transmitted infections clinic. METHODS: We conducted a retrospective study of virologically proven first-episode genital herpes diagnosed in the Department of Genitourinary Medicine in Edinburgh between 1989 and 2002. RESULTS: First-episode anogenital herpes was associated with HSV-1 in 659 (62%) women and 294 (42%) men (P <0.0002). HSV-1 was recovered more often from women younger than 25 years than from older women (P <0.0005). For both HSV-1 and HSV-2 infections, the median ages of heterosexual men (26.0 and 28.0 years, respectively) were significantly higher than those of women (23.0 and 25.0 years, respectively)(P <0.05). The median age of men who have sex with men with HSV-1 (29.0 years) was significantly higher than that of heterosexual men (26.0 years)(P <0.01). CONCLUSION: HSV-1 remains the most common cause of symptomatic first-episode anogenital herpes, especially among young women in our clinic population.

Adult↗

Detection of herpes simplex virus DNA in serum and oral secretions during acute recurrent herpes labialis.

Although herpes simplex virus (HSV) has been detected in the peripheral blood of immunocompromised patients and in neonates with disseminated disease, the extent to which the virus may be present in the blood during a localized infection in otherwise healthy patients is still unknown. Literature on patterns of HSV shedding into the oral cavity at the prodromal stage of the disease, during recurrences, and also during asymptomatic periods is still lacking. The present study aims at the detection of HSV DNA in the serum and oral secretions during acute herpes labialis using a highly sensitive technique, the polymerase chain reaction (PCR). The study included 10 patients with acute herpes labialis and five healthy controls. Using PCR, herpes simplex virus DNA was detected in the serum of seven patients (70%) and in the saliva of nine patients (90%). One of the control cases showed positive HSV DNA in the saliva (20%). There was good statistical agreement between the presence of HSV DNA in the serum and saliva. Frequency of attacks, patient's age, and gender had no statistically significant effect on the presence of the virus in serum or in saliva. It is concluded that HSV viremia during attacks of recurrent herpes simplex is more frequent than previously appreciated.

Acute Disease↗

Grappling with herpes: herpes gladiatorum.

Initial reports of herpes gladiatorum, a skin infection of wrestlers caused by herpes simplex virus (HSV), focused on case histories and clinical presentations of this disease. To more adequately address broader epidemiologic questions concerning this skin infection, we surveyed members of four southeastern college wrestling teams, sampled high school and college athletic trainers nationwide, and obtained serum specimens from members of one college wrestling team for HSV antibody studies. Nine of 48 (18.8%) college wrestlers in the southeastern athletic conference reported histories of herpes gladiatorum. Wrestlers with a prior history of oral HSV infection (cold sores) were less likely to report HSV skin infection than wrestlers without cold sores (RR = 0.25; 95% C.I. 0.03 to 1.8), while wrestlers with exposure to opponents with cutaneous HSV lesions were at high risk to develop herpes gladiatorum (RR = 9.4; 95% C.I. 2.2 to 40.0). The national survey of athletic trainers indicated that 7.6% of college wrestlers and 2.6% of high school wrestlers had HSV skin infection during the 1984-85 season. Herpes gladiatorum is a common problem among college wrestlers, and morbidity associated with this skin disease can be significant.

Adolescent↗

Importance of herpes simplex virus type-1 (HSV-1) in primary genital herpes.

Herpes simplex virus type 1 (HSV-1) is increasingly reported in primary genital herpes. Its incidence was assessed among Rotterdam sexually transmitted diseases clinic attendees between 1996 and 2001, and demographic and sexual behaviour factors were evaluated. A retrospective record analysis was performed. All herpes diagnoses were based on cell culture techniques. A clinical scoring system was used to select "primary" cases. Demographic and sexual behaviour characteristics were analysed using logistic regression. The clinical scoring system showed 115 cases of primary genital herpes. HSV-1 (n = 60) was found in 52% and HSV-2 (n = 55) in 48% of cases. The multiple logistic regression model showed that HSV-1 was associated with "oro-genital contact" (p < 0.001) and "having a single partner in the last 2 months" (p = 0.054) and that HSV-2 was associated with "a higher number of sexual partners in the last 6 months" (p = 0.085). Our data confirm the growing importance of HSV-1 in primary genital herpes; oro-genital sex is the main risk factor.

Adolescent↗

[Polymorphism of herpes simplex virus type 1 and 2 DNA from laboratory strains and clinical material from patient with genital herpes].

Polymerase chain reaction (PCR), that can amplify a fragment of the DNA-polymerase gene of 4 herpes viruses, i.e. herpes simplex viruses, type 1 (HSV-1), herpes simplex viruses, type 2 (HSV-2), Epstein-Barr virus and cytomegalovirus, was made use of to study the genetic polymorphism of HSV-1 and HSV-2 strains. The obtained amplicons were analyzed by the method of restriction-size fragments' polymorphism (RSFP) with restrictases Rsal, Taql and Hinfl. Four HSV-1 strains had an identical restriction profile. Strain G (HSV-2) also displayed the expected restriction profiles, however, contradictory results were obtained for strain BH (HSV-2): the restriction profiles with restrictases Hinfl and Rsal corresponded to HSV-2, and the restriction profile with Taql corresponded to HSV-1. The sequencing of appropriate fragments of strains G and BH revealed a dot-type mutation localized in Taql restriction site. The thus worked out PCR was used jointly with RSFP in the genotyping of 75 urogenital samples obtained from women with genital herpes who were treated at Moscow patient-care facilities. HSV-1 and HSV-2 were detected in 18 (24%) and 57 (76%) of samples, respectively. No changes were registered in the restriction profile for HSV-2 among the investigated samples and all of them had the restriction profile similar to that of strain G. The conclusion is that genital herpes associated with HSV-2 is genetically stable within its Moscow population.

Animals↗

Seroepidemiology and control of genital herpes: the value of type specific antibodies to herpes simplex virus.

Herpes simplex virus (HSV) type 2 is the main cause of genital herpes infections. Conventional serological techniques cannot discriminate between antibodies specific to HSV types 1 and 2, so these methods cannot be used in the seroepidemiological investigation of genital herpes infections. The discovery of type specific antigens in HSV-1 and HSV-2, most notably glycoprotein G (gG), has been successfully exploited to develop assays for the detection of type specific HSV antibody. The presence of type specific antibodies provides evidence for infection with HSV-1, HSV-2, or both. Tests which detect humoral responses to HSV-2 have been used during the past decade to investigate populations in various countries. Most surveys of general adult populations in the developed world have found a relatively low seroprevalence of HSV-2, although this does differ between countries. Studies of HSV-2 antibody in developing countries have revealed higher rates of infection in adults. People attending sexually transmitted diseases (STD) clinics have higher rates of HSV-2 infection than general populations sampled in the same country. Assays of HSV type specific antibodies have been used in seroepidemiological surveys that include information about demography and sexual behaviour to identify risk factors for HSV-2 infection. The surveys show that people with a large number of sexual partners are at increased risk of acquiring HSV-2 infection and that a high proportion of HSV-2 infections are asymptomatic. Assays of HSV type specific antibody have been used to show that the presence of pre-existing HSV-1 antibody may reduce the severity of genital HSV-2 infection. Such assays have also been used in studies of the transmission of genital herpes. Proposed interventions to counter the spread of genital herpes include targeted education and vaccination programmes. Assays of HSV type specific antibodies may be used to monitor the effectiveness of such policies.

Adult↗

Ribonucleotide reductase of herpes simplex virus type 2 resembles that of herpes simplex virus type 1.

The ribonucleotide reductase (ribonucleoside-diphosphate reductase; EC 1.17.4.1) induced by herpes simplex virus type 2 infection of serum-starved BHK-21 cells was purified to provide a preparation practically free of both eucaryotic ribonucleotide reductase and contaminating enzymes that could significantly deplete the substrates. Certain key properties of the herpes simplex virus type 2 ribonucleotide reductase were examined to define the extent to which it resembled the herpes simplex virus type 1 ribonucleotide reductase. The herpes simplex virus type 2 ribonucleotide reductase was inhibited by ATP and MgCl2 but only weakly inhibited by the ATP X Mg complex. Deoxynucleoside triphosphates were at best only weak inhibitors of this enzyme. ADP was a competitive inhibitor (K'i, 11 microM) of CDP reduction (K'm, 0.5 microM), and CDP was a competitive inhibitor (K'i, 0.4 microM) of ADP reduction (K'm, 8 microM). These key properties closely resemble those observed for similarly purified herpes simplex virus type 1 ribonucleotide reductase and serve to distinguish these virally induced enzymes from other ribonucleotide reductases.

Adenosine Triphosphate↗

Preventing neonatal herpes. The value of weekly viral cultures in pregnant women with recurrent genital herpes.

To reduce the occurrence of neonatal herpes, laboratory screening with viral cultures during the last four to eight weeks of pregnancy has been recommended as a way to recognize women with subclinical herpes infection at delivery. Screening efforts have focused on a group of high-risk women, especially those with recurrent genital herpes infection. Using the technique of decision analysis, we examined the benefits, risks, and costs of viral culture screening for women with recurrent genital herpes. In a cohort of 3.6 million women, we estimate that screening would avert 11.3 neonatal deaths and 3.7 cases of severe retardation, but 3.3 women would die as a result of cesarean deliveries necessitated by culture results. Weekly viral cultures would diagnose one fourth of women with subclinical recurrent infection at delivery. The cost per case averted would be approximately $1.8 million. Future screening recommendations should consider not only the number of cases averted but also the effectiveness of screening and the costs in both maternal lives and medical care dollars.

Cesarean Section↗

Demonstration of either endogenous recurrence or exogenous reinfection by restriction endonuclease cleavage analysis of herpes simplex virus from patients with recrudescent genital herpes.

By using restriction endonuclease (RE) cleavage analysis, either endogenous recurrence or exogenous reinfection of herpes simplex virus (HSV) was clarified in 45 male and 20 female subjects with recrudescent genital herpes. All of the plural (two to ten) isolates from 63 (205 isolates) out of 65 subjects (97%) were HSV-2. Two isolates from only one of 65 subjects (1.5%) were HSV-1, and they showed the same RE profile. In addition, an HSV-1 and five HSV-2 isolates were obtained from the remaining one female patient (1.5%), indicating that an exogenous HSV-1 strain has been reinfected during HSV-2 recrudescences. HSV-2 isolates were furthermore classified into genotypes of HSV-2 using 16 different RE markers with five REs. Two hundred and ten HSV-2 isolates from 64 subjects were classified into 27 distinct genotypes, in which some predominant genotypes and seven new genotypes were found. Plural HSV-2 isolates obtained from 63 out of 64 subjects, including one subject from whom an HSV-1 and five HSV-2 strains were isolated, were classified into the same genotypes, indicating that they may be regarded as recrudescent genital herpes by the reactivation of the same endogenous strain. However, the RE profiles of two HSV-2 strains from the remaining one subject were different. Thus, it was finally found that only two out of 65 subjects (3%) were reinfected with exogenous strains. These results lead to the conclusion that almost all recrudescent genital herpes are due to the reactivation of an initially infected HSV-2 strain, and are occasionally due to reinfection with distinct HSV strains of either the same or a different type.

Adult↗

Longitudinal evaluation of herpes simplex virus DNA load during episodes of herpes labialis.

BACKGROUND: Few studies have performed sequential evaluation of the herpes simplex virus (HSV) load using quantitative PCR during episodes of herpes labialis. OBJECTIVE: To determine HSV viral load kinetics during recurrences of herpes labialis. STUDY DESIGN: Twenty-two subjects were monitored by daily swabs during recurrences of herpes labialis. A real-time PCR detecting both HSV-1 and HSV-2 was used to quantify the viral load. RESULTS: Median duration of HSV-1 shedding was 60 h and 48 h by PCR and culture, respectively. No HSV-2 DNA was detected in that study. Peak viral DNA load (123.6 copies/cell) occurred at 48 h with no virus detected beyond 96 h of onset of symptoms. CONCLUSIONS: These viral load kinetics data could be used as surrogate markers of antiviral activity in future clinical trials.

Adult↗

A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects.

BACKGROUND: A replication incompetent herpes virus lacking the glycoprotein H gene has been developed as a potential therapeutic vaccine for genital herpes. GOAL: To determine vaccine efficacy on reducing HSV reactivation and clinical disease among immunocompetent persons with recurrent genital HSV-2 infection. STUDY DESIGN: Randomized multicenter placebo-controlled trial. Healthy volunteers who had six or more recurrences of genital herpes per year were randomized to receive injections of vaccine at 0 and 8 or 0, 4, and 8 or 0, 2, 4, and 8 weeks or placebo and were followed for subsequent recurrences for 1 year. RESULTS: The median times to first recurrence of genital herpes (40 days versus 30 days versus 37 days versus 42 days, respectively), mean number of recurrences (3 versus 3 versus 2.4 versus 1.9, respectively), and time to lesion healing of the first recurrence (8 days versus 7.8 days versus 7.4 days versus 7.5 days, respectively), were similar for all treatment groups. Asymptomatic viral shedding was detected by PCR in 61/74 (82%) persons performing daily sample collection following completion of the vaccination series. No differences were noted in the proportion of days with shedding between treatment groups (11.9% versus 17.2% versus 13.1% versus 16.4%, respectively). CONCLUSION: This replication incompetent HSV-2 vaccine lacking the glycoprotein H gene was safe but had no clinical or virologic benefit in the amelioration of genital HSV-2 disease among immunocompetent men and women.

Adolescent↗

[Efficacy and tolerability of acyclovir in immunosuppressed patients with herpes simplex, herpes zoster or cutaneomucous chicken-pox. Multicenter trial apropos of 50 cases].

A multicenter trial of Acyclovir was carried out in 50 immunodepressed patients. The dose used was 15 mg/kg/day for 5 days in herpes simplex and 30 mg/kg/day for 10 days in herpes zoster and chicken pox by three one-hourly intravenous infusion per day. Acyclovir had a clear cut effect in 42 cases, a partial effect in 1 case, no effect in 1 case, and its action could not be assessed in 6 cases. The cutaneous and mucous membrane lesions were stabilised after an average of two days' treatment, and regression was observed from the third day. Of the 21 cases of zoster, 15 were cured without sequellae and 5 with post-zoster pain. The treatment failed in one patient. Of the 21 cases of cutaneous and/or mucous membrane herpes simplex, 20 satisfactory and 1 partial result were obtained. The outcomes of the 2 cases of chicken pox were favourable. There were three relapses after the end of therapy (2 herpes simplex, 1 zoster) but their outcomes were favourable after a second course of Acyclovir. In 20 cases it was possible to maintain the immuno-suppressive therapy. General tolerance was satisfactory.

Acyclovir↗

Famiciclovir therapy (famvir) for herpes simplex and herpes zoster infections.

Genital herpes simplex and herpes zoster infections are common afflictions that are associated with significant morbidity and a decreased quality of life. Famciclovir (Famvir, Novartis) is an orally administered prodrug of the antiviral agent penciclovir. Its unique pharmacokinetic profile makes it an efficacious, convenient and well-tolerated alternative to the traditionally prescribed acyclovir. Famciclovir is used for the acute treatment and suppressive therapy of recurrent genital herpes as well as for herpes zoster and its debilitating comorbidities. Famiciclovir allows patients to manage or prevent symptoms, thereby significantly improving their quality of life. Its favorable safety profile makes it a good treatment choice for the elderly as well as for immunocompromised patients, including those infected with HIV.

2-Aminopurine↗

In vitro induction of human cell-mediated cytotoxicity directed against herpes simplex virus-infected cells. Kinetics in normal donors and patients with recurrent herpes labialis.

In order to analyse cellular cytotoxic mechanisms involved in herpes virus infections, human peripheral blood mononuclear leukocytes (PBML) were incubated (sensitized) for up to 7 days with uninfected or herpes simplex virus type 1 (HSV-1)-infected cells. The sensitized PBML were then tested in a 5-hr 51Cr-release microassay against uninfected, HSV-1-infected, or cytomegalovirus (CMV)-infected target cells. PBML from normal donors, sensitized with HSV-1 infected cells, exhibited strong cytotoxicity against these same cells, but not against CMV-infected target cells. Peak cytotoxic activity was found after 6 days of sensitization. In contrast, PBML from herpes patients showed an earlier (3 days) and a higher cytotoxic response than normal PBML. In both groups however, maximal stimulation of lymphocyte transformation was observed at 6 days, suggesting that the early cytotoxic response in herpes patients could be an in vitro correlate of an anamnestic, or secondary response.

Adult↗

Herpes zoster in the first year of life following postnatal exposure to varicella-zoster virus: four case reports and a review of infantile herpes zoster.

BACKGROUND: Herpes zoster, a painful vesicular dermatomal eruption, is the result of reactivation of the varicella-zoster virus (VZV) from infected sensory ganglia. Traditionally, it is considered to be a disease of adults, in contrast to primary infection with VZV, which tends to occur mainly in children. OBSERVATIONS: We report 4 cases of infantile herpes zoster in healthy immunocompetent children, all of whom were exposed to primary varicella infection within the first few months of life. A review of 62 cases from the literature reveals that postnatally acquired herpes zoster is less common than intrauterine infection (31% [n = 19] vs 69% [n = 43]) and that there is a 1.5:1 male predominance. All dermatomes are equally affected. CONCLUSIONS: Although uncommon, herpes zoster can develop in immunocompetent children as young as a few weeks of age and should be considered in the differential diagnosis of vesicular eruptions in infants. Most frequently, it is the result of intrauterine VZV infection, but it can be secondary to postnatal exposure to VZV at an early age.

Diagnosis, Differential↗