Herpes simplex virus type I-infected disorders alter the balance between Treg and Th17 cells in recurrent herpes labialis patients.

Recurrent herpes labialis (RHL) is a common skin disease that is often caused by herpes simplex virus type I (HSV-1), but its immunology and pathogenesis remain unclear. The balance of Th17/Treg cells is crucial for maintaining immune homeostasis. This study aimed to investigate whether the balance of Th17/Treg cells and related cytokines may be a determinant occurrence in patients with RHL. This is a clinical experimental research based on clinical observation and analysis. We collected RHL patients from the outpatient clinic of the Department of Dermatology of Zhejiang Chinese Medical University (Hangzhou, China) in 2017, conducted questionnaire survey and signed informed consent. Peripheral blood was collected from 30 patients with RHL and 30 healthy volunteers. Flow cytometry was used to detect the percentages of Treg cells and Th17 cells. Protein microarrays coated with 20 cytokines related to T-cell subsets were performed. Enzyme-linked immunosorbent assay (ELISA) assay was conducted to further verify the expression levels of the cytokines that were screened by protein microarrays. Percentages of Th17/Treg cells in peripheral blood of RHL patients were significantly increased compared to those in healthy volunteers. The fold changes of GM-CSF, IL-4, TGF-ß, IL-12, IL-10, IL-17F, and TNF-α were significantly increased compared with healthy volunteers. In addition, the expression of IL-4, IL-10, and TGF-ß in the serum of RHL patients increased significantly. Our results indicated an imbalance of Th17/Treg cells in RHL, and this imbalance is probably an important factor in the occurrence, development, and recovery of RHL.

Vitamin D Levels in Patients with Recurrent Herpes Labialis.

Recurrent infections of herpes simplex virus in the orolabial area are known as recurrent herpes labialis (RHL). Vitamin D has been shown to have an important immunomodulatory role and to be associated with several infectious diseases. This hospital-based case-control study aimed at investigating the association between vitamin D and RHL by comparing vitamin D levels in individuals with and without RHL. Individuals who presented to the dermatology clinic at a state hospital due to RHL (n = 50) and matching control group of healthy volunteers (n = 51) were studied. Their vitamin D levels were measured, stratified based on clinical guidelines, and compared. The average serum vitamin D (25-hydroxyvitamin D) levels were 23.8 ± 15.5 and 42.0 ± 26.3 nM in the patient and control groups, with significant differences between their average serum vitamin D levels and vitamin D status. The studied population had serious vitamin D deficiency regardless of having RHL, with vitamin D levels below the adequate limits in more than 96% of the population. Most importantly, the study established a significant association between low serum vitamin D levels and the presence of RHL. Further interventional and pathophysiological studies should clarify the nature and mechanism of the relationship.

Immune characteristics correlating with HSV-1 immune control and effect of squaric acid dibutyl ester on immune characteristics of subjects with frequent herpes labialis episodes.

INTRODUCTION: Differences in immune characteristics, including immune gene expression by peripheral blood mononuclear cells (PBMCs), correlating with herpes labialis and good or poor immune control of herpes simplex virus type 1 (HSV-1), and how these characteristics change after dosing with squaric acid dibutyl ester (SADBE), were investigated. METHODS: PBMCs were collected from persons positive for IgG against HSV-1 and having frequent, infrequent, or no herpes labialis outbreaks. The PBMCs were tested for proliferation against HSV-1 and a fungal antigen (Candida) and immune gene expression in the presence of HSV-1 and Candida. On day 1 after blood collection the subjects with frequent outbreaks were dosed topically on the arm once with SADBE, and their PBMCs were collected and tested 8 weeks later. RESULTS: Those with good immune control of their HSV-1 infection (fewer outbreaks) differ from those with poorer immune control in these ways: (1) Greater PBMC proliferation in vitro to HSV-1, HSV-1-infected cell extracts, and Candida considered together (P < 0.01). (2) Higher expression of IFNG and five other immune-related genes (P < 0.05 for each) and lower expression of IL5 and two other immune-related genes (P < 0.05 for each) in PBMCs in vitro stimulated with HSV-1 virus. The subjects with frequent outbreaks were treated once with SADBE, and 56 days later the PBMCs of these subjects differed from PBMCs from the same subjects taken on day 1 before treatment in exactly the same ways listed above as differences between those with good and poor immune control of HSV-1, and at the same levels of significance. CONCLUSIONS: Higher IFNG and lower IL5 expression by PBMCs in the presence of HSV-1 correlate with fewer herpes labialis outbreaks, and a single topical dose of SADBE to the arm of subjects with frequent herpes labialis episodes improves immune response to HSV-1.

Viral Genetics Modulate Orolabial Herpes Simplex Virus Type 1 Shedding in Humans.

BACKGROUND: Orolabial herpes simplex virus type 1 (HSV-1) infection has a wide spectrum of severity in immunocompetent persons. To study the role of viral genotype and host immunity, we characterized oral HSV-1 shedding rates and host cellular response, and genotyped viral strains, in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 29 MZ and 22 DZ HSV-1-seropositive twin pairs were evaluated for oral HSV-1 shedding for 60 days. HSV-1 strains from twins were genotyped as identical or different. CD4+ T-cell responses to HSV-1 proteins were studied. RESULTS: The median per person oral HSV shedding rate was 9% of days that a swab was obtained (mean, 10.2% of days). A positive correlation between shedding rates was observed within all twin pairs, and in the MZ and DZ twins. In twin subsets with sufficient HSV-1 DNA to genotype, 15 had the same strain and 14 had different strains. Viral shedding rates were correlated for those with the same but not different strains. The median number of HSV-1 open reading frames recognized per person was 16. The agreement in the CD4+ T-cell response to specific HSV-1 open reading frames was greater between MZ twins than between unrelated persons (P = .002). CONCLUSION: Viral strain characteristics likely contribute to oral HSV-1 shedding rates.

[Cycloferon and management of herpes virus infection].

The treatment of patients with various forms of herpes requires a complex approach with using chemo- and immunotropic drugs. The use of Cycloferon, an interferon inductor (12.5% injection solution, 150 mg tablets or 5% liniment) was shown efficient. It had antiviral and immunotropic action in the mono- and combination therapy of herpes simplex of the skin and mucosa, genital herpes, ophthalmoherpes, herpes zoster, infectious mononucleosis. Cycloferon lowered the level and period of the disease clinical signs, prolonged the remission, corrected the immunity shifts, prevented the complications. The results of the study presented a conclusive proof for recommending such a use of Cycloferon in wide medical practice.

Recent approval of Xerese in Canada: 5% acyclovir and 1% hydrocortisone topical cream in the treatment of herpes labialis.

Herpes labialis is a frequently occurring viral infection of the lips and oral mucosa. Recurring lesions are induced by viral reactivation and replication, but the symptoms leading to morbidity, such as pain and inflammation, are immune-mediated. The introduction of 5% acyclovir/1% hydrocortisone in a topical cream (Xerese™) represents a therapeutic strategy directed at both of these pathogenic processes. Applied at the onset of prodromal symptoms, this combination treatment has a good safety profile and is more effective in reducing healing time than antiviral or anti-inflammatory agents alone. Although it was US FDA-approved for herpes labialis in 2009, Xerese™ has only recently been approved for use in Canada in October 2013. Herein, we review the basic science and clinical studies that support the efficacy of this topical combination acyclovir-hydrocortisone product in treating herpes labialis and examine its safety profile, as well as touch upon other therapies that have been shown to be effective in treating this common viral condition.

Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine.

A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(∗)24, HLA-B(∗)27, HLA-B(∗)53 and HLA-B(∗)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(∗)44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy.

[Using cycloferon in the complex treatment of herpetic infection in patients with atopic dermatitis].

Clinical efficacy of including cycloferon liniment in combined treatment of herpetic infection in a group of 40 patients with atopic dermatitis has been analyzed. It is concluded that the administration of cycloferon favors dynamic disappearance of general infectious syndrome, reduces timeline of rash as well as length of local inflammation, accelerates epithelization of erosions (on the average 1.2 - 1.4 times, p < 0.05), decreases frequency of recurrent infections, and reduces the level of pro-inflammatory cytokines in the blood of patients.

Herpes simplex primo-infection in an immunocompetent host with eosinophilic esophagitis.

Eosinophilic esophagitis and herpes simplex esophagitis are separately well-described entities, but their simultaneous occurrence may pose a special challenge to the clinician, especially regarding the optimal therapeutic approach. The following case report describes a patient with a history of cow's milk and dairy products intolerance, but without an underlying immunologic defect, in whom eosinophilic esophagitis was diagnosed in the course of primary herpes simplex virus 1 (HSV1) infection that clinically presented as herpes labialis and severe esophagitis. The diagnosis was confirmed by a polymerase chain reaction from cytological brush and by immunohistochemical staining that detected the presence of HSV1 DNA in esophageal mucosa, and histologically by persistent eosinophil-predominant inflammation, typical of eosinophilic esophagitis. Despite severe clinical presentation, the HSV1 infection was self-limited. After a directed elimination diet was introduced, the clinical course was favorable, without the need for antiviral therapy.

Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis.

HSV-1 persistently infects almost 90% of our population; however, only 30% of the infected subjects suffer from recurrent herpes lesions, most frequently herpes labialis (HL). We hypothesized that variations in toll-like receptor (TLR) functions might contribute to HL susceptibility. In our study, the TLR-2/1,-3, and -7/8 responses of immune cell subsets derived from asymptomatic HSV-1 carriers were compared with responses of subjects with HL history. Remarkably, natural killer (NK) cells isolated from HL subjects showed significantly lower IFN-γ responses selectively to the TLR3 agonist poly(I:C). Furthermore, the TLR3 L412F genetic polymorphism was found to reduce NK cell TLR3-responsiveness and is associated with susceptibility to recurrent HL. The TLR3 response detected in HL total peripheral blood mononuclear cells (PBMCs), however, was not impaired, indicating restoration of NK cell TLR3-deficiency through co-stimulatory functions. In conclusion, our results suggest that decreased TLR3 response of NK cells is associated with HL susceptibility; and potentially explain why symptomatic outbreak of HL usually occurs after stress or prolonged UV light exposure, when host co-stimulatory functions are disturbed.

Long-term remission of recurrent herpes labialis following topical imiquimod application on distant healthy skin: a clinical and immunological study.

BACKGROUND: Given the limitations of current antiviral therapies, safer and more effective approaches to the management of recurrent herpes labialis (RHL) are needed. METHODS: A patient with a 23-year history of RHL and 14 healthy individuals were studied. The patient applied imiquimod to distant healthy skin for 3 weeks. Peripheral blood (PB) samples were collected from the patient during treatment and 21 months after its discontinuation; samples were collected from the controls once. The distribution of lymphocyte populations in PB were analysed by flow cytometry and PB cytokine levels were measured using cytometric bead arrays. RESULTS: The patient showed long-term remission of the disorder subsequent to a 3-week imiquimod application to distant healthy skin. Imiquimod treatment induced the activation and proliferation of T-helper and cytotoxic T-cells, B-cells and T-regulatory cells. In addition, there was a very strong transient increase of T-helper 1 cells (resulting in interferon-γ secretion) and type 1 (pro-inflammatory) polarization of the immune response accompanied by a sustainable interferon-α production. At follow-up 21 months after treatment cessation, with the patient remaining relapse-free, the patient had control levels of all cytokines, increased levels of activated cytotoxic T-cells, continuous production of new T-helper cells and B-cells and near-to-normal levels of T-regulatory cells. CONCLUSIONS: Our results indicate that topical application of imiquimod to healthy skin is capable of causing systemic immunomodulation. This treatment might represent a new and effective alternative to established therapeutic and prophylactic regimens for RHL.

Interferon-lambda in immunocompetent individuals with a history of recurrent herpes labialis.

BACKGROUND: Herpes labialis (HL) is the most common manifestation of recurrent oral herpes simplex virus type-1 (HSV-1) infection. Between 20% and 40% of the population is affected by recurrent HL. The biological basis for the difference between HSV-1-infected individuals who do and who do not suffer recurrences, has long been investigated. Interferon (IFN)-alpha and IFN-lambda are essential for antiviral immunity, but the precise role of IFN-lambda in vivo is not yet well understood. METHODS: Healthy immunocompetent patients with or without a history of recurrent HL were recruited from the Policlinico of the University of Rome Tor Vergata (Rome, Italy), and HSV-1-seronegative individuals were recruited from the Department of Experimental Medicine of the University of Rome Tor Vergata, between July 2007 and December 2008. Participants were interviewed by medically trained investigators and underwent a blood test. Peripheral blood mononuclear cells (PBMCs) were obtained from heparinized blood of patients and stimulated in vitro with intact HSV-1 strain F1 (1 plaque-forming unit/cell). PBMC supernatants were assayed for IFN-alpha, IFN-gamma and IFN-lambda production by ELISA at 24 and 48 h after viral challenge. RESULTS: PBMC from patients with a history of recurrent HL produced markedly lower levels of IFN-lambda and marginally lower levels of IFN-alpha and IFN-gamma than those from the history-negative HSV-1-seropositive controls. Among individuals with HL recurrences, those with more frequent and severe manifestations showed a significant trend towards lower levels of IFN-lambda production. CONCLUSIONS: A reduced IFN-lambda response might correlate with the development of recurrent HSV-1 infection in immunocompetent individuals. Testing for IFN-lambda response might be useful to predict individual patterns of antiviral response, contributing to more successful therapeutic or prophylactic interventions.

Estudio del efecto inmunomodulador de la Equinácea purpúrea en pacientes con herpes labial recurrente / Imunomodulatory effects of Echinacea purpurea in patients with recurrent herpes labialis

Introducción: El Herpes Labial Recurrente supone una condición inmunológica alterada, tal como una hiperactividad de células T-reguladoras CD4+CD25+ (Treg). Éstas ejercen control sobre la tolerancia periférica y reducen el riesgo inmunopatológico, suprimiendo otras líneas celulares. Por ende, la supresión ejercida sobre la reacción inmune antiviral podría afectar negativamente el curso de la infección. Este contexto ha impulsado la búsqueda de nuevas alternativas inmunomoduladoras como la Equinácea purpúrea. Dada su propiedad inmunosupresora, se propone en el tratamiento del Herpes Labial Recurrente. Metodología: Estudio clínico prospectivo que analiza las subpoblaciones linfocitarias en 12 pacientes con Herpes Labial Recurrente, antes y después de recibir Equinácea purpúrea (30 gotas tres veces al día durante siete días).Resultados: En comparación con individuos sanos, los pacientes presentan una respuesta aumentada de células Treg. Esta condición se reduce significativamente tras recibir Equinácea purpúrea (515 + 145 y 432 + 113 cel/mm3 antes y después del tratamiento, respectivamente, p < 0,005). Conclusión: La hiperactividad de células Treg podría explicar el estado de inmunosupresión de estos pacientes y favorecería la persistencia viral. Se propone esta fitomedicina como una alternativa inmunoterapéutica beneficiosa.

Background: Recurrent Herpes Labialis patients may suffer from immunological alterations, such as CD4+CD25+Regulatory-T Cell (Treg) hyperactivity. These cells control peripheral tolerance and reduce immunopathology risk by suppressing other immunological cells. Hence, the Treg cell suppression on the antiviral immune reaction may perturb adversely the herpes infection outcome. This scenario has forced physicians to explore new immunomodulatory alternatives in Phytomedicine, such as Echinacea purpurea. Regarding the immunosuppressive property, it has been challenged to be employed in the Recurrent Herpes Labialis management. Methods: Clinical prospective study that analyzed lymphocytic subpopulation profile in twelve patients with Recurrent Herpes Labialis, before and after receiving E. purpurea (30 drops three times a day during seven days). Results: Comparing to healthy subjects, patients presented an enlarged Treg cell response. This condition became significantly reduced after receiving E. purpurea. (515 + 145 and 432 + 113 cel, before and after treatment respectively, p < 0.005). Conclusion: The intensified Treg cell activity may elucidate the immune suppression these patients undergo, aiding the viral persistence and survival. This proposes E. purpurea asa beneficial immunotherapeutic alternative.

Recurrent infections in patients with nickel allergic hypersensitivity.

Nickel (Ni) is the most common contact allergen among the general population in the industrialized world. Ni has been shown to exhibit immunomodulatory, if not immunotoxic, effects in several experiments conducted on humans and on rodents. This study tests the incidence of different infectious diseases in 100 patients with Ni hypersensitivity and compares it to data from 100 healthy volunteers. One hundred subjects with Ni hypersensitivity were enrolled. A group of 100 matched healthy volunteers with negative European standard patch test were enrolled as healthy controls. In patients with Ni hypersensitivity a higher incidence of recurrent herpes labialis (RHL), urinary tract infections (RUTI), genital candidiasis, and upper respiratory tract infections (RURTI) was detected. Fifteen patients with nickel allergic hypersensitivity (NAH) followed a Ni-poor diet. After a one-year diet a net reduction of incidence of RHL was found. Indeed, the number of episodes of RHL per year decreased from 6 +/- 2.75 to 2.4 +/- 1.2. Conversely, among the matched control group with NAH following a normal daily dietary nickel intake the RHL number did not show any statistically significant changes (6.1 +/- 1.7 vs 6 +/- 1.5 ). In conclusion, our study demonstrates a higher incidence of recurrent infections among patients with NAH. A low-Ni diet reduces the number of RHL episodes per year.

An update on short-course intermittent and prevention therapies for herpes labialis.

Infection with herpes simplex virus (HSV) has increased in prevalence worldwide over the past two decades, making it a major public health concern. Approximately 90% of recurrent HSV type 1 (HSV-1) infections manifest as non-genital disease, primarily as orofacial lesions known as herpes labialis. Improvements in our understanding of the natural history of herpes labialis support the rationale for early treatment (during the prodrome or erythema stages) with high doses of antiviral agents in order to maximize drug benefit. When evaluating the efficacy of different antiviral and anti-inflammatory agents in clinical trials, episode duration, lesion healing time, reduction in maximum lesion size and the proportion of aborted lesions should be used as the most reliable measures of therapeutic efficacy. There has also been considerable research into the most beneficial treatment for recurrent episodes of herpes labialis in immunocompetent individuals. Data from clinical studies confirm that short-course, high-dose oral antiviral therapy should be offered to patients with recurrent herpes labialis to accelerate healing, reduce pain and most likely increase treatment adherence. Optimal benefits may be obtained when these oral antiviral agents are combined with topical corticosteroids, but more research is needed with this combination. Patients undergoing facial cosmetic procedures (i.e.facial resurfacing) are at risk of HSV reactivation, but further data are required on the actual risk according to the specific procedure. Aciclovir, valaciclovir and famciclovir all provide effective prophylaxis against HSV-1 reactivation following ablative facial resurfacing. However, no definitive recommendations can be made regarding prophylactic therapy for minimally invasive procedures at present.