Recurrent Herpes Simplex Virus Infection Research Articles

Polymorphisms of thymidine kinase gene in herpes simplex virus type 1: analysis of clinical isolates from herpetic keratitis patients and laboratory strains.

Drug-resistance of herpes simplex virus (HSV) is caused most frequently by mutation of the viral thymidine kinase (TK) gene. To elucidate the significance of detecting nucleotide changes of the TK gene for screening drug-resistant viruses, the frequency and variation of the genetic polymorphisms in the whole coding region of the TK gene were studied in 14 acyclovir-susceptible HSV type 1 (HSV-1) clinical isolates from 14 patients with epithelial herpetic keratitis. Two reference HSV-1 laboratory strains, McKrae and PH, and two acyclovir-resistant variants of the PH strain were also studied as controls. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing detected nucleotide differences at 24 positions, and amino acid substitutions at 12 codons in the TK gene of the examined viruses. Nucleotide diversity of 0.0029 per base (the average number of nucleotide substitutions of 3.3 per 1,131 base pairs) in the TK gene in the clinical isolates was comparable to 0.0037 per base of the whole HSV-1 genome in Japanese isolates reported previously. PCR-SSCP analysis of the acyclovir-resistant strains easily detected aberrantly shifted bands by comparing them with those of the parental strain, followed by the quick determination of mutated sequences. These results suggest that detection of nucleotide changes of the TK gene is useful for serial observation of persistent or recurrent HSV infection as observed in immunocompromised hosts, but that it is not useful for screening drug-resistant viruses from nonepidemic clinical isolates because of the comparable genetic polymorphisms in the TK gene as in the whole HSV-1 genome.

Infection of the corneal endothelium in herpes simplex keratitis

PURPOSE: To describe viral infection of the corneal endothelium in a patient with recurrent herpes simplex virus keratitis in the corneal graft. METHODS: Case report. A healthy 28-year-old man presented with necrotizing stromal keratitis and corneal perforation in the corneal graft. A second penetrating keratoplasty was performed. The corneal button was processed for histopathologic, immunohistochemical, and electron microscopic studies. RESULTS: Histopathologically, the corneal endothelium showed viral inclusion bodies. Herpes simplex virus antigens and viral particles were identified in stromal keratocytes and corneal endothelial cells. CONCLUSION: Productive herpes simplex virus infection of the corneal endothelial cells may contribute to corneal graft failure in recurrent herpes simplex virus infections.

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy

Objective: The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir. Study Design: In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks’ gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants. Results: Peak acyclovir plasma concentrations (mean ± standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 ± 0.7 μg/mL vs 0.74 ± 0.6 μg/mL, P < .0001) and at steady state (3.03 ± 1.0 μg/mL vs 0.94 ± 0.7 μg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 ± 3.6 h · μg/mLvs 7.71 ± 2.5 h · μg/mL, P < .001) and at steady state (19.65 ± 6.4 h · μg/mL versus 11.0 ± 4.5 h · μg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected. Conclusion: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy. (Am J Obstet Gynecol 1998;179:846-51.)

Recognition of Herpes Simplex Virus Type 2 Tegument Proteins by CD4 T Cells Infiltrating Human Genital Herpes Lesions

The local cellular immune response to herpes simplex virus (HSV) is important in the control of recurrent HSV infection. The antiviral functions of infiltrating CD4-bearing T cells may include cytotoxicity, inhibition of viral growth, lymphokine secretion, and support of humoral and CD8 responses. The antigens recognized by many HSV-specific CD4 T cells localizing to genital HSV-2 lesions are unknown. T cells recognizing antigens encoded within map units 0. 67 to 0.73 of HSV DNA are frequently recovered from herpetic lesions. Expression cloning with this region of DNA now shows that tegument protein VP22 and the viral dUTPase, encoded by genes UL49 and UL50, respectively, are T-cell antigens. Separate epitopes in VP22 were defined for T-cell clones from each of three patients. Reactivity with the tegument protein encoded by UL21 was identified for an additional patient. Three new epitopes were identified in VP16, a tegument protein associated with VP22. Some tegument-specific CD4 T-cell clones exhibited cytotoxic activity against HSV-infected cells. These results suggest that herpes simplex tegument proteins are processed for antigen presentation in vivo and are possible candidate compounds for herpes simplex vaccines.

Development of antiviral therapeutic agents from traditional medicines

Traditional medicines contain various metabolites derived from nucleic acid, protein, and lipid metabolism. Some of these specific metabolites may recognize the differences between viral and host metabolism resulting in anti-viral activity; hence traditional medicines may be useful sources for new antiviral agents. Traditional medicines can be cheaply obtained and have been orally administered as hot-water extracts. Therefore, they may be used for the prophylactic and therapeutic treatment of viral infection by drinking them, such as coffee or tea. Here we describe how the antiviral activity of traditional medicines was screened in vitro and how their therapeutic antiviral activities were verified in vivo, to obtain traditional antiviral medicines that can be clinically used. Therefore, we have selected 12 herbal extracts, from more than 250 herbal medicines, that exhibit therapeutic activities against cutaneous herpes simplex virus (HSV) type 1 (HSV-1) infection in mice. Four of the 12 augmented the therapeutic efficacy of acyclovir (ACV) in mice and showed potent anti-HSV activity against infection with ACV-resistant HSV-1 mutants in mice. These herbal extracts selectively inhibited viral DNA synthesis and showed a different mode of anti-HSV-1 action from that of ACV. They were also effective against both recurrent HSV and cytomegalovirus infections, without toxicity. Such prophylactic and therapeutic antiviral activities of the traditional medicines were verified by the purification of major active compounds. We could show new indications of traditional medicines as antiviral agents. Thus, the drinking of the extracts, in a daily tea or coffee, may be used for prophylaxis and therapy of diseases caused by herpes virus infection and improve the quality of life.

Distribution of herpes simplex virus types 1 and 2 genomes in human spinal ganglia studied by PCR and in situ hybridization

Clinical data indicate that the recurring herpes simplex virus (HSV) from oro-labial lesions is HSV subtype 1 and that the virus from genital lesions is HSV-2. This suggests that HSV-1 and HSV-2 reside in latent forms in the trigeminal ganglia and sacral ganglia, respectively. However, the distribution of latent HSV-1 and HSV-2 infections in human spinal ganglia has not been fully examined. This report concerns the application of polymerase chain reaction (PCR) and in situ hybridization (ISH) to such a study. By using PCR and employing the respective primers, HSV-1 and HSV-2 DNAs were detected in 207 of 524 samples from 262 spinal ganglia (from the cervical to the sacral ganglia) examined on both sides. The percentages of HSV-1 and HSV-2 detected in a given set of ganglia were similar, indicating an absence of site preference. By ISH, few but positive hybridization signals were detected evenly in sacral ganglia sections. The data suggest that regional specificity of recurrent HSV infections is not due to regional distribution of latent virus, but that local host factors may be important for recurrences.

Defective functional behaviour peripheral blood mononuclear cells from patients with recurrent herpes simplex virus infection

Defective functional behaviour peripheral blood mononuclear cells from patients with recurrent herpes simplex virus infection

Defective functional behaviour peripheral blood mononuclear cells from patients with recurrent herpes simplex virus infection

Defective functional behaviour peripheral blood mononuclear cells from patients with recurrent herpes simplex virus infection

Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group.

OBJECTIVE: To determine the efficacy and safety of once daily valaciclovir for the suppression of recurrent genital herpes simplex virus (HSV) infection in immunocompetent patients. METHODS: 382 otherwise healthy patients...

Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group.

OBJECTIVE: To compare the efficacy and safety of twice daily valaciclovir with five times daily aciclovir in the treatment of an episode of recurrent genital herpes simplex virus (HSV) infection...

Neonatal herpes in Denmark 1977-1991.

To prevent neonatal herpes, women in labor with genital herpes infection are still delivered by Cesarean section. This policy is currently being debated. The aim of this study was to determine the incidence of neonatal herpes in Denmark and to evaluate the prevention practice. All newborns with perinatal herpes in Denmark 1977-1991 were identified from hospital-records. Of 862,298 deliveries 136 possible cases were found but only 30 (22%) fulfilled the criteria for neonatal herpes. The incidence increased from 2.36 to 4.56 per 100,000 live births during 1977-1984 through 1984-1991. Three mothers (10%) had recurrent herpes at delivery, three (10%) had primary herpes, and five (17%) had oral herpes. Seven infants (23%) were delivered by Cesarean section. Nine (30%) only had cutaneous herpes, four (13%) had CNS herpes, nine (30%) had disseminated disease. Six (20%) did not have any sequelae. Four (13%) died. Six (20%) had serious neurological sequelae. Seven (23%) only had cutaneous recurrences. In seven cases (23%) information was insufficient. During a 15 year period in Denmark only one neonate had serious sequelae following a recognized maternal herpes recurrence. Four infants had a serious infection in spite of Cesarean section. This study does not support a policy of Cesarean section in case of maternal recurrent herpes simplex infection at delivery.

Quantitation of herpes simplex virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis by the polymerase chain reaction

Background: Previous studies have shown the diagnostic utility of qualitative detection of herpes simplex virus (HSV) DNA by the polymerase chain reaction (PCR) in cerebrospinal fluid samples (CSF) from patients with herpes simplex encephalitis (HSE). Objectives: To determine whether quantitation of HSV DNA in CSF could be useful for monitoring efficacy of antiviral therapy and provide prognostic indications. Study design: A quantitative PCR assay using an internal control for evaluation of PCR efficiency and detection of PCR inhibitors was developed and used for retrospective testing of 98 CSF samples from 26 patients with serologically diagnosed HSE during the period 1980–1995. Results: HSV DNA was detected in 36 CSF samples from 23 patients. PCR positivity was 100% for CSF samples collected within 10 days after onset, and 30.4 and 18.7% for samples collected 11–20 and 21–40 days later, respectively. The 3 PCR-negative patients had their first CSF collected 14, 16, and 28 days after onset, respectively. Three of 98 (3.1%) CSF samples were completely or partially inhibitory to PCR. Initial DNA levels were not significantly different in patients with HSE due to either primary or recurrent HSV infection. In addition, they were not related to severity of clinical symptoms nor were predictive of the outcome. A progressive decrease in viral DNA levels was observed both in patients who received acyclovir therapy and in a small number of untreated patients. Conclusions: This study: (i) confirms the high sensitivity of PCR for the diagnosis of HSE; (ii) emphasizes the need for an internal control of amplification to achieve maximal sensitivity and perform reliable quantitation of viral DNA; and (iii) suggests that CSF might not be the best specimen to investigate in studies of the natural history of HSE.

Mucormycosis in a Patient With Acquired Immunodeficiency Syndrome

Mucormycosis classically affects patients who are immunocompromised or debilitated, including those with diabetes, malignant neoplasm, renal failure, and neutropenia. 1 Despite the opportunistic nature of mucormycosis infection, there are few cases of cutaneous manifestations of the infection reported in patients with the acquired immunodeficiency syndrome (AIDS). 2-5 We describe a patient with AIDS, neutropenia, and iron overload who developed primary cutaneous mucormycosis. In addition, the patient had recently undergone intralesional chemotherapy and radiation treatments on his face for Kaposi sarcoma. Report of a Case. A 41-year-old white man with AIDS manifested by a CD4 cell count below 10×10 9 /L and a medical history that included disseminated Kaposi sarcoma, cytomegalovirus retinitis, recurrent herpes simplex infection, anemia, and adrenal insufficiency was admitted to the hospital with acute onset of right-sided facial pain and swelling. His facial Kaposi sarcoma had been treated previously with intralesional doxorubicin hydrochloride and radiation. On

The metabolic roles, pharmacology, and toxicology of lysine.

L-lysine monohydrochloride (LMH) is widely available to the public as a nonprescription oral supplement. Most of the pharmaceutical-grade product is used as a suppressant of recurrent herpes simplex infections. Recent publications indicate the possibility of other therapeutic uses, e.g., in cardiovascular disease and osteoporosis. These and other potential applications are surveyed and evaluated in this review with suggestions for further study. Data on toxicity are reviewed and recommendations made regarding safety of chronic dosage levels.

Long-term Oral Acyclovir Therapy: Effect on Recurrent Infectious Herpes Simplex Keratitis in Patients with and without Grafts

To evaluate the efficacy of long-term oral acyclovir therapy in reducing recurrences of dendritic or geographic herpes simplex keratitis (HSK). Thirteen patients with a history of frequently recurring HSK were followed before (mean, 27 months) and during long-term systemic acyclovir, and eight were followed after the acyclovir was discontinued. Treatment ranged from 8.5 to 62 months (mean, 34 months). During treatment, the number of recurrences per month decreased from 0.15 to 0.03, and the average duration of relapses decreased from 12.6 to 7.8 days. Recurrences correlated with daily doses of oral acyclovir of 800 mg or less, intraocular surgery within 6 weeks of initiating treatment, and discontinuation of therapy against medical advice. The results of this small study appear to demonstrate the efficacy of long-term oral acyclovir in prophylaxis of recurrent epithelial herpes simplex infection: therapeutic doses of oral acyclovir reduce both the rate and duration of recurrences of infectious herpetic keratitis. A multicenter, double-masked, placebo-controlled study is indicated.

Prophylactic efficacy of traditional herbal medicines against recurrent herpes simplex virus infection in mice and guinea pigs: M. Kurokawa 1, M. Nakano 1, H. Ohyama 2, T. Hozumi 2, T. Namba 1, T. Kawana 3 and K. Shiraki 1. 1Toyama Medical and Pharmaceutical University, Toyama, 2Showa Shell Sekiyu K.K., Kanagawa and 3Tokyo University Branch Hospital, Tokyo, Japan

Fialuridine (FIAU) is a thymidine nucleoside analog with activity against various herpesviruses and hepatitis B virus (HBV) in vitro and in vivo. In a clinical evaluation for its use as a treatment for chronic HBV infection, long term oral administration of FIAU resulted in severe multi-organ toxicity characterized by a delayed onset and refractory lactic acidosis. These clinical manifestations led to the hypothesis that the toxicity of FIAU was mediated through mitochondrial dysfunction, possibly as a result of the inhibition of mitochondrial DNA polymerase γ and/or incorporation of FIAU into mitochondrial DNA. In addition to describing the anti-HBV activity of FIAU, this review discusses results from in vitro experiments carried out by various laboratories in an effort to evaluate and understand more fully the mitochondrial toxicity of FIAU.

Therapeutic immunization for recurrent herpes simplex virus infections.

Two centuries ago Jenner dramatically demonstrated the power of vaccines for disease prevention. He protected individuals from the deadly smallpox virus by injecting them with vesicular fluid from cowpox lesions. Currently, vaccines are used world-wide as primary tools for preventing infectious diseases. In addition to this traditional role, some investigators today think vaccines can be used to treat diseases. Other scientists disagree.1 Skeptics argue that vaccines cannot boost the immune response better than the natural infection itself In the case of recurrent herpes simplex virus (HSV) infections, the virus reactivates periodically in spite of natural immunity. To be useful therapeutically, then, a vaccine would have to present herpes antigens to the immune system in a different, more effective way than they are presented by natural recurrences. Data emerging from vaccine therapy of patients with recurrent HSV infections suggests that vaccines can be used to treat disease.

Immunological Studies of herpes simplex virus infection in children with atopic eczema

This study examines the role of immune defence mechanisms in herpes simplex virus (HSV) infections in atopic eczema and whether impairment of these mechanisms explains the susceptibility of some children with atopic eczema to cutaneous HSV infections. Ten children with eczema herpeticum and 13 with atopic eczema and recurrent HSV infection affecting multiple skin sites were studied, together with relevant control groups. In all children with atopic eczema, in vitro lymphoproliferation in response to stimulation with concanavalin A (Con A) was significantly decreased and natural killer (NK) cells (CD16 + 56) were reduced compared with non-atopic controls. IL-2 receptors, a marker for lymphocyte activation, were decreased during the acute phase of eczema herpeticum, and for 1 month thereafter. A positive stimulation index (> 3) to HSV antigen, and high HSV IgG antibody titres measured by ELISA, Western blotting and neutralization assay, were seen in children with eczema herpeticum by 6 weeks, and also in children with atopic eczema and recurrent HSV infections. No evidence of an HSV-specific immune defect (either cell-mediated or humoral) was found in atopic eczema. Impairment of cell-mediated immunity in atopic eczema was suggested by the reduced response to Con A. It is likely that reduced numbers of circulating NK cells and a decrease in IL-2 receptors during early eczema herpeticum contribute to the susceptibility of children with atopic eczema to cutaneous HSV infections.

Valacyclovir

Valacyclovir is the l-valyl ester prodrug of acyclovir and exhibits similar potency, but has more favorable pharmacokinetic characteristics, requiring a less frequent dosing schedule and achieving higher blood plasma levels than acyclovir. With the acyclovir prodrugs, the physical properties such as water or lipid solubilities (log P) are not major determinants of the most effective bioavailability. The structure-activity relationship of the amino acid esters suggests the involvement of a stereospecific transport process. The common branched chain amino acids, l-valine and l-isoleucine, are favored by this proposed transporter. 2 Acyclovir is a derivative of guanosine. A critical step in its activation is phosphorylation by viral thymidine kinase. The affinity of acyclovir for herpes virus-encoded thymidine kinase is approximately 200 times greater than for human thymidine kinase, and phosphorylation of acyclovir by the human enzyme occurs at a negligible rate. This selective affinity results in the activation and concentration of acyclovir in virus-infected cells. After phosphorylation to acyclovir monophosphate (acyclo-GMP), normal cellular enzymes catalyze the sequential phosphorylation to acyclovir diphosphate (acyclo-GDP) and acyclovir triphosphate (acyclo-GTP). Acyclovir triphosphate terminates the production of viral DNA by inhibiting DNA polymerase via competition with deoxyguanosine triphosphate; it has selective affinity for viral DNA polymerase. In addition, acyclo-GTP is incorporated into the elongating viral DNA, where it causes termination of the viral DNA strand. 3,4,5 After oral administration, valacyclovir is rapidly absorbed and extensively converted to acyclovir via first-pass metabolism. Acyclovir has been detected in plasma as early as 15 min after the valacyclovir administration. Oral administration results in plasma acyclovir concentrations approximately 3- to 5-fold greater than those achievable with comparable oral doses of acyclovir. 6,7,8 The elimination half-life of acyclovir is approximately 3 h; acyclovir is primarily excreted unchanged in the urine. Valacyclovir appears to be a significant development in antiviral therapy. Its significantly greater oral bioavailability results in plasma acyclovir levels comparable to those seen with intravenous acyclovir. Although acyclovir has been effective in immunocompetent patients with mucocutaneous herpes simplex virus (HSV) infection, the need for multiple daily dosing has been problematic. With a higher C max after valacyclovir administration, less frequent dosing may be equally effective, both for acute treatment and for suppression. In the treatment of recurrent genital herpes simplex infections, valacyclovir 1,000 mg orally twice a day for 5 days has been effective. In patients receiving the drug within 24 h of initiation of signs and symptoms, valacyclovir was as effective as acyclovir in reducing time to lesion healing and length of episode. 9 Herpes zoster (shingles) patients treated with oral valacycyclovir report complete cessation of postherpetic pain in a statistically shorter time than patients treated with oral acyclovir; the two drugs have a similar time to rash healing. Valacyclovir has been approved for marketing in the U.S.A. as a treatment for shingles in immunocompetent patients. Valacyclovir was first launched in the U.K. and Ireland in January 1995, and has since been launched in Sweden.

Prevention of recurrent herpes simplex virus (HSV) infections in HIV-infected persons.

The purpose of this study was to determine the frequency of HSV infections and recurrences among HIV-infected patients and to examine different regimens for suppression of HSV recurrence. A randomized retrospective chart review of HIV-infected patients at a public hospital in Los Angeles County was conducted. We reviewed 224 patients' charts; 26 percent had AIDS based on the 1987 CDC definition. HSV infection was documented as a clinical event in 51 records (23 percent). Patients with an AIDS diagnosis had a greater incidence (53 percent) of HSV infections than did those with a diagnosis of symptomatic or asymptomatic HIV infection (p < 0.001, Fisher's exact test). Recurrences of HSV occurred in 26 (51 percent) of the 51 HSV-infected persons during a period of 1042 patient months. Eighteen patients who had received acyclovir suppression at 600 mg/day had three HSV recurrences in 382 patient months, whereas 14 who received 400 mg/day had eight recurrences in 282 patient months (p = 0.02). HSV infections occur in 23 percent of HIV-infected patients, increasing to 53 percent in AIDS patients. Acyclovir suppression prevents recurrent HSV, and a dosage of 600 mg/day is more effective than 400 mg/day.