Associations between host genetic variants and Herpes Simplex Labialis in the TwinsUK cohort.

OBJECTIVE: Previous literature supports controversial results about the role of host genetic factors in the reactivation of Herpes Simplex Labialis (HSL). The objective of this study is to explore the association between different putative single nucleotide polymorphisms (SNPs) and self-reported HSL reactivation in the TwinsUK cohort. DESIGN: 1761 participant were recruited for this study from the TwinsUK register. Blood collection and HSL questionnaire were completed for a subset of 595 participants (age 61.9, dizygotic twins 62.8%). Blood was stored at -80 °C and DNA analysed from all samples. The potential associations between candidate SNPs and HSL were assessed using a set of 40 SNPs, including SNPs previously correlated with HSL disease and other SNPs previously associated with the oral microbiota. RESULTS: 235 participants reported to have experienced 'cold sores' at least once in their lives, and 160 reported reinfection episodes. No association was detected between rs243588, rs1047978, rs1062202 genotypes and both occurrence of cold sores (p = 0.172, p = 0.360, p = 0.742) and their recurrence (p = 0.160, p = 0.105,p = 0.746). Among other investigated SNPs, a nominal significant association was detected between Vitamin D Receptor (VDR) Fok I (rs2228570) and both history of HSL (p = .001) and its recurrence (p = .007). CONCLUSIONS: A single nucleotide polymorphism in the VDR gene may be correlated with cold sores and their recurrence.

Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections.

Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.

Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes.

IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women's Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)-infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV-1 and HSV-2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV-2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV-1 and 79.0% were positive for HSV-2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV-1 or HSV-2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV-2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV-2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.

Therapeutic low-intensity red laser for herpes labialis on plasmid survival and bacterial transformation.

A low-intensity laser is used in treating herpes labialis based on the biostimulative effect, albeit the photobiological basis is not well understood. In this work experimental models based on Escherichia coli cultures and plasmids were used to evaluate effects of low-intensity red laser on DNA at fluences for treatment of herpes labialis. To this end, survival and transformation efficiency of plasmids in E. coli AB1157 (wild type), BH20 (fpg/mutM(-)) and BW9091 (xthA(-)), content of the supercoiled form of plasmid DNA, as well as nucleic acids and protein content from bacterial cultures exposed to the laser, were evaluated. The data indicate low-intensity red laser: (i) alters the survival of plasmids in wild type, fpg/mutM(-) and xthA(-)E. coli cultures depending of growth phase, (ii) alters the content of the supercoiled form of plasmids in the wild type and fpg/mutM(-)E. coli cells, (iii) alters the content of nucleic acids and proteins in wild type E. coli cells, (iv) alters the transformation efficiency of plasmids in wild type and fpg/mutM(-)E. coli competent cells. These data could be used to understand positive effects of low-intensity lasers on herpes labialis treatment.

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.

C21orf91 genotypes correlate with herpes simplex labialis (cold sore) frequency: description of a cold sore susceptibility gene.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) infects >70% of the United States population. We identified a 3-megabase region on human chromosome 21 containing 6 candidate genes associated with herpes simplex labialis (HSL, "cold sores"). METHODS: We conducted single nucleotide polymorphism (SNP) scans of the chromosome 21 region to define which of 6 possible candidate genes were associated with cold sore frequency. We obtained the annual HSL frequency for 355 HSV-1 seropositive individuals and determined the individual genotypes by SNPlex for linkage analysis and parental transmission disequilibrium testing (ParenTDT). RESULTS: Two-point linkage analysis showed positive linkage between cold sore frequency and 2 SNPs within the C21orf91 region, 1 of which is nonsynonymous. ParenTDT analysis revealed a strong association between another C21orf91 SNP, predicted to lie in the 3' untranslated region, and frequent HSL (P = .0047). C21orf 91 is a predicted open reading frame of unknown function that encodes a cytosolic protein. CONCLUSIONS: We evaluated candidate genes in the cold sore susceptibility region using fine mapping with 45 SNP markers. 2 complementary techniques identified C21orf91 as a gene of interest for susceptibility to HSL. We propose that C21orf91 be designated the Cold Sore Susceptibility Gene-1 (CSSG1).

Interrelationship between ultraviolet light and recurrent herpes simplex infections in man.

In humans, epicutaneous application of a universally sensitizing dose (2000 micrograms) of dinitrochlorobenzene (DNCB) to skin exposed to 4 consecutive daily doses (144 mJ/cm2) of ultraviolet-B radiation (UVB) induces contact hypersensitivity (CH) in approximately 56% of normal, adult individuals (UVB-resistant--UVB-R), but not in the remaining 44% (UVB-susceptible--UVB-S). In patients with biopsy proven basal/squamous cell cancer, the frequency of the UVB-S trait exceeds 90%, indicating that this phenotype may be a risk factor for sunlight-induced skin cancer. Since many patients with recurrent herpes labialis complain that lip lesions are precipitated by acute sun exposure, we wondered whether the UVB-S trait might be associated with this recurrent disease. A group of 31 volunteers was selected, each with a history of numerous episodes of labialis secondary to reactivated herpes simplex virus-1 infection. Subjects were questioned carefully concerning factors, including sun exposure, thought to be important in precipitating lip lesions. Each individual was then subjected to the UVB plus DNCB protocol. When forearm skin of these individuals was assayed for CH after 30 days, 20 (65%) proved to be UVB-S (approximately 1.5 times the expected frequency), while the remainder displayed vigorous DNCB-specific CH. A strong history of sun-induced recurrent herpes simplex labialis did not predict the UVB phenotype. A subset of these subjects was exposed to 2 MEDs of UVB to their faces. None of the UVB-R subjects developed recurrent herpes labialis while 6 of 8 UVB-S subjects developed recurrent lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-sectional study of recurrent herpes labialis. Prevalence and risk factors.

Consecutive blood donors at 25 sites in southern Wisconsin were interviewed in 1985 to ascertain recurrent herpes labialis histories, other perioral conditions, and status on possible predisposing factors and correlates of lesion recurrence. The prevalence of recurrent herpes labialis was 32.9%. Of the cases, 51.3% reported at least two recurrences per year, 8.6% characterized their condition as severe, and 10% sought medical care. Relations were examined between recurrent herpes labialis and family history of the disease, ethnicity, complexion, hair and eye color, other chronic perioral conditions, solar radiation, exposure to dental procedures, and smoking. The risk of recurrent herpes labialis associated with disease in various first-degree family members, estimated by age-adjusted odds ratios (nominal 95% confidence intervals) were: mother, 3.30 (1.86-5.84); father, 3.80 (1.80-8.12); sister(s), 3.93 (2.25-6.89); and brother(s), 6.81 (3.14-15.04). Ethnicity and phenotypes were not related to disease status. Cases had a higher prevalence of recurrent aphthous ulcers (odds ratio = 3.00, 95% confidence interval = 1.79-5.02) and reported more exposure to solar radiation and more extensive dental histories.

MHC-linked genetic factors (HLA-B35) influencing recurrent circumoral herpetic lesions.

The frequencies of HLA-A, B, C, DR, and DQ lymphocyte alloantigens were determined in 31 Sicilian patients with recurrent herpetic lesions (RHL) and compared to frequencies observed in normal individuals. A significant negative association was found for HLA-B35 (pc = 0.049). The relationships between HLA and immune responses to viral infections are discussed in light of the results revealed by the present investigation suggesting that HLA-linked genetic factors may play a role in the pathogenesis of RHL. The results seem to indicate that genes in the major histocompatibility complex (MHC) are influential against developing RHL.

Chromosomal breaks and sister chromatid exchanges (SCE) in patients with herpetic stomatitis.

Chromosomal breakage and sister-chromatid exchanges (SCE) were studied in peripheral lymphocytes of 9 patients with primary herpetic stomatitis (PHS), 12 patients with secondary herpetic stomatitis (SHS) and 12 controls. The incidence of chromosomal breakage was significantly higher in PHS patients (mean 23%, P. = 0.0002) and in SHS patients (mean 20.25%, P. = 0.0003) compared to the controls (mean 4.2%). The incidence of SCE per 46 chromosomes was significantly higher in SHS patients (mean 16.564) compared with (P. less than 0.001) the controls (mean 11.367) and compared with (P. = 0.006) the PHS patients (mean 12.131). It is concluded that both PHS and SHS patients exhibit structural chromosomal damage; SHS patients in addition exhibit more repaired chromosomal lesions.

Disseminated neonatal herpes simplex virus infection acquired from the father.

A disseminated herpes virus type 1 infection in a baby was acquired from the father, who had herpes labialis. This was shown by virus strain typing using restriction endonuclease DNA analysis. Labial herpes, a common infection in adults, must be recognised as a potential threat to newborn babies.

Stress as a precipitating factor in subjects with recurrent herpes labialis.

The model of recurrent herpes labialis was selected to evaluate the role played by stress in increasing susceptibility to illness. Initially, 35 paid volunteers with recurrent herpes were enrolled in the project. Compared with 35 age- and sex-matched controls, this group demonstrated a familial predisposition for recurrent herpes labialis. Eighteen subjects without confounding variables known to precipitate recurrent herpes infections completed a pretested "stress" questionnaire during a dormant and again during an active stage of infection. In the week prior to the appearance of a recurrence, this group experienced increased daily hassles, increased stressful life events, and higher state anxiety. These findings are discussed in the broader context of stress-associated disease with some speculations concerning a possible biologic mechanism, which involves modulations of T-lymphocyte function.