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Herpes simplex virus 2 (HSV-2) is a sexually transmitted infection affecting 491 million individuals globally. Consequently, there is a great need for both prophylactic and therapeutic vaccines. Unfortunately, several vaccine clinical trials, primarily employing the glycoprotein D of HSV-2 (gD-2), have failed. The immune protection conferred by human anti-HSV-2 antibodies in genital infection and disease remains elusive. It is well-known that gD-2 elicits cross-reactive neutralizing antibodies, i.e., anti-gD-2 antibodies recognize gD in HSV-1 (gD-1). In contrast, anti-glycoprotein G in HSV-2 (mgG-2) antibodies are exclusively type-specific for HSV-2. In this study, truncated versions of gD-2 and mgG-2 were recombinantly produced in mammalian cells and used for the purification of anti-gD-2 and anti-mgG-2 antibodies from the serum of five HSV-2-infected subjects, creating a pool of purified antibodies. These antibody pools were utilized as standards together with purified mgG-2 and gD-2 antigens in ELISA to quantitatively estimate and compare the levels of cross-reactive anti-gD-1 and anti-gD-2 antibodies, as well as anti-mgG-2 antibodies in sera from HSV-1+2-, HSV-2-, and HSV-1-infected subjects. The median concentration of anti-mgG-2 antibodies was five times lower in HSV-1+2-infected subjects as compared with cross-reactive anti-gD-1 and anti-gD-2 antibodies, and three times lower in HSV-2 infected subjects as compared with anti-gD-2 antibodies. The pool of purified anti-gD-2 antibodies presented neutralization activity at low concentrations, while the pool of purified anti-mgG-2 antibodies did not. Instead, these anti-mgG-2 antibodies mediated antibody-dependent cellular cytotoxicity (ADCC) by human granulocytes, monocytes, and NK-cells, but displayed no complement-dependent cytotoxicity. These findings indicate that antibodies to mgG-2 in HSV-2-infected subjects are present at low concentrations but mediate the killing of infected cells via ADCC rather than by neutralizing free viral particles. We, and others, speculate that Fc-receptor mediated antibody functions such as ADCC following HSV-2 vaccination may serve as a better marker of protection correlate instead of neutralizing activity. In an mgG-2 therapeutic vaccine, our findings of low levels of anti-mgG-2 antibodies in HSV-2-infected subjects may suggest an opportunity to enhance the immune responses against mgG-2. In a prophylactic HSV-2 mgG-2 vaccine, a possible interference in cross-reactive immune responses in already infected HSV-1 subjects can be circumvented.

AbstractInitial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naïve patients were randomized to receive efavirenz (EFV) (n= 74), lopinavir/ritonavir (LPV/r) (n= 77), or atazanavir/ritonavir (ATV/r) (n= 79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoctests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45–2.73), 2.42 (2.27–2.57), and 2.13 (2.01–2.25) log10copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p< 0.0001), and with LPV/r at days 7–21 (p< 0.0001–0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p= 0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p = 0.003) or ATV/r (p< 0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor–based regimens. The observed differences may reflect different inherent regimen potencies. [ABSTRACT FROM AUTHOR]

Herpes simplex virus 2 (HSV-2) is a sexually transmitted infection affecting 491 million individuals globally. Consequently, there is a great need for both prophylactic and therapeutic vaccines. Unfortunately, several vaccine clinical trials, primarily employing the glycoprotein D of HSV-2 (gD-2), have failed. The immune protection conferred by human anti-HSV-2 antibodies in genital infection and disease remains elusive. It is well-known that gD-2 elicits cross-reactive neutralizing antibodies, i.e., anti-gD-2 antibodies recognize gD in HSV-1 (gD-1). In contrast, anti-glycoprotein G in HSV-2 (mgG-2) antibodies are exclusively type-specific for HSV-2. In this study, truncated versions of gD-2 and mgG-2 were recombinantly produced in mammalian cells and used for the purification of anti-gD-2 and anti-mgG-2 antibodies from the serum of five HSV-2-infected subjects, creating a pool of purified antibodies. These antibody pools were utilized as standards together with purified mgG-2 and gD-2 antigens in ELISA to quantitatively estimate and compare the levels of cross-reactive anti-gD-1 and anti-gD-2 antibodies, as well as anti-mgG-2 antibodies in sera from HSV-1+2-, HSV-2-, and HSV-1-infected subjects. The median concentration of anti-mgG-2 antibodies was five times lower in HSV-1+2-infected subjects as compared with cross-reactive anti-gD-1 and anti-gD-2 antibodies, and three times lower in HSV-2 infected subjects as compared with anti-gD-2 antibodies. The pool of purified anti-gD-2 antibodies presented neutralization activity at low concentrations, while the pool of purified anti-mgG-2 antibodies did not. Instead, these anti-mgG-2 antibodies mediated antibody-dependent cellular cytotoxicity (ADCC) by human granulocytes, monocytes, and NK-cells, but displayed no complement-dependent cytotoxicity. These findings indicate that antibodies to mgG-2 in HSV-2-infected subjects are present at low concentrations but mediate the killing of infected cells via ADCC rather than by neutralizing free viral particles. We, and others, speculate that Fc-receptor mediated antibody functions such as ADCC following HSV-2 vaccination may serve as a better marker of protection correlate instead of neutralizing activity. In an mgG-2 therapeutic vaccine, our findings of low levels of anti-mgG-2 antibodies in HSV-2-infected subjects may suggest an opportunity to enhance the immune responses against mgG-2. In a prophylactic HSV-2 mgG-2 vaccine, a possible interference in cross-reactive immune responses in already infected HSV-1 subjects can be circumvented.

The diagnosis of genital lichen sclerosus (LS) is often confirmed by obtaining a skin biopsy, which can lead to unwanted complications and is uncomfortable in the sensitive genital area. Thus, there is a need of finding novel, non-invasive techniques that can rapidly and accurately diagnose LS. The present study investigated the potential for reflectance confocal microscopy (RCM) to diagnose LS compared with healthy penile skin and other common penile skin disorders in males. A total of 30 male patients, including patients with LS, nonspecific balanoposthitis, plasma cell balanitis and psoriasis, and healthy individuals were included and were subject to non-invasive RCM investigation. Prominent fiber-like structures, representing hyaline sclerosis, were observed in the RCM images for almost half of the patients. Differences between healthy penile skin and LS were confirmed by identifying the edged papillae on healthy skin and their absence or obscureness in patients with LS. Notably, RCM could detect the atypical honeycomb pattern referring to dysplasia in 1 patient with LS with penile intraepithelial neoplasia. In conclusion, the present study demonstrated that RCM can detect sclerosis in penile LS. RCM can potentially become a valuable tool for monitoring patients with LS for dysplasia providing a useful non-invasive diagnostic tool for genital disorders., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kantere et al.)

The incidence of syphilis was decreasing during the last decades of the 20th century, partly due to the awareness and fear of hiv. However, an increase is now apparent in many countries. It is still uncommon in Sweden compared to chlamydia and gonorrhoea, and the incidence is 4.6/100.000 inhabitants. The infection can be latent and without symptoms, but also manifest itself as a painless genital ulcer, with rash and fever, or as neurosyphilis. Congenital infection due to transmission of the syphilis spirochete from an infected mother to her fetus is still a problem in many parts of the world. In order to prevent congenital syphilis it is important for all pregnant women to have access to maternal care during their pregnancy, and to get efficient treatment if diagnosed with syphilis.

IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor proposed to act in the cyclic GMP-AMP synthase-stimulator of IFN genes pathway. Because mice do not have a clear ortholog of IFI16, this system is not suitable for genetic studies of IFI16. In this study, we have compared the dependency on IFI16, cyclic GMP-AMP synthase, and stimulator of IFN genes for type I IFN induction by a panel of pathogenic bacteria and DNA viruses. The IFN response induced by HSV-2 was particularly dependent on IFI16. In a cohort of patients with genital herpes and healthy controls, the minor G allele of the IFI16 single nucleotide polymorphism rs2276404 was associated with resistance to infection. Furthermore, the combination of this allele with the C allele of rs1417806 was significantly overrepresented in uninfected individuals. Cells from individuals with the protective GC haplotype expressed higher levels of IFI16 and induced more IFN-β upon HSV-2 infection. These data provide genetic evidence for a role for IFI16 in protection against genital herpes., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.

Objective: To investigate asymptomatic shedding from the uterine cervix of five human herpes viruses: cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) type 1 and type 2 and varicella zoster virus (VZV), in young women., Design: A descriptive study., Setting: Sahlgrenska University Hospital., Population: Three hundred and five young, healthy Swedish women., Methods: Cervical specimens were analyzed for the presence of viral DNA with a quantitative real-time PCR assay., Main Outcome Measures: Detection of viral DNA., Results: Viral DNA was detected in 66 (21.6%) of the cervical samples. The most common findings were CMV DNA, detected in 35 (11.5%), and EBV DNA, found in 32 (10.5%) of the women. HSV-1 DNA was detected in 5 (1.7%) and HSV-2 DNA in 4 (1.4%), but VZV DNA was not found. The estimated DNA level for the detected viruses was similar with a mean DNA quantity of 2.6 log genome equivalents (Geq)/mL for CMV (range 1.7-4.3), 2.5 log Geq/mL for EBV (range 1.7-4.7), 2.4 log Geq/mL for HSV-1 (range 1.7-3.5) and 2.6 log Geq/mL for HSV-2 (range 1.7-4.1). The simultaneous presence of DNA from two or more herpes viruses was detected in eight specimens., Conclusions: Asymptomatic shedding of CMV and EBV from the uterine cervix was found in one-fifth of young women. In four of the cervical samples; two with EBV, one with CMV, one with HSV-2, high amounts of viral DNA (>4 log Geq/mL) were detected suggesting a greater risk of transmitting the virus perinatally or sexually., (© 2013 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-γ) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-γ-mediated protection against HSV-2 infection in mice. In a cohort of 228 HSV-2-infected individuals, representing both patients with recurrent disease and asymptomatic HSV-2 carriers, we found that genetic variations in the STAT4 gene were associated with asymptomatic HSV-2 infection, as well as with increased in vitro secretion of IFN-γ in response to the virus. Mice that lacked STAT4 had impaired HSV-2-specific IFN-γ production and delayed-type hypersensitivity responses following vaccination, which led to impaired viral clearance in the genital tract of vaccinated animals after a genital HSV-2 challenge. We conclude that STAT4 plays an important role in IFN-γ-mediated HSV-2-specific immunity, affecting the severity of genital HSV-2 infection.

Lack of Toll-like receptor 3 (TLR3) functional activity predisposes children to human herpesvirus 1 (HSV-1) encephalitis. In this study, we have investigated whether there is any link between TLR3 and adult HSV-2 infection by studying genetic variations in TLR3. The frequency of four single-nucleotide polymorphisms (SNPs) in the TLR3 gene in 239 patients with genital HSV-2 infection and 162 healthy controls, as well as the impact of these variants on TLR3 gene-expression levels, were compared. Two SNPs in the TLR3 gene (rs13126816 and rs3775291) were associated with a reduced incidence of HSV-2 infection. The minor allelic variants at both rs13126816 and rs3775291 were more common among healthy HSV-2-seronegative subjects than among HSV-2-infected individuals. This was even more apparent in HSV-1-seronegative individuals. There was, however, no association between any of the four TLR3 SNPs and HSV-2 disease severity, as they were expressed at similar proportions in asymptomatic and symptomatic HSV-2-infected patients alike. Furthermore, when assessing TLR3 mRNA expression in a limited number of HSV-2-infected individuals, we found that individuals carrying the homozygous genotypes for the minor alleles had significantly higher levels of TLR3 mRNA expression in peripheral blood mononuclear cells in response to HSV-2 stimulation than individuals that were homozygous for the major allele variants. Taken together, these results suggest that genetic variations in TLR3 may affect the susceptibility to HSV-2 infection in humans.

Initial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naïve patients were randomized to receive efavirenz (EFV) (n = 74), lopinavir/ritonavir (LPV/r) (n = 77), or atazanavir/ritonavir (ATV/r) (n = 79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoc tests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45-2.73), 2.42 (2.27-2.57), and 2.13 (2.01-2.25) log(10) copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p < 0.0001), and with LPV/r at days 7-21 (p < 0.0001-0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p = 0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p = 0.003) or ATV/r (p < 0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor-based regimens. The observed differences may reflect different inherent regimen potencies.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen infecting most individuals worldwide. The majority of HSV-1-infected individuals have no clinical symptoms but shed HSV-1 asymptomatically in saliva. Recent phylogenetic analyses of HSV-1 have defined three genetic clades (A-C) and recombinants thereof. These data have all been based on clinical HSV-1 isolates and do not cover genetic variation of asymptomatically shed HSV-1. The primary goal of this study was to investigate such variation. A total of 648 consecutive saliva samples from five HSV-1-infected volunteers was collected. Asymptomatic shedding was detected on 7.6 % of the days from four subjects. The HSV-1 genome loads were quantified with real-time PCR and varied from 1x10(2) to 2.8x10(6) copies of virus DNA (ml saliva)(-1). Phylogenetic network analyses and bootscanning were performed on asymptomatically shed HSV-1. The analyses were based on DNA sequencing of the glycoprotein I gene, and also of the glycoprotein E gene for putative recombinants. For two individuals with clinical HSV-1 infection, the same HSV-1 strain was shed asymptomatically as induced clinical lesions, and sequence analyses revealed that these strains clustered distinctly to clades A and B, respectively. For one of the subjects with no clinical HSV-1 infection, a recombinant strain was identified. The other truly asymptomatic individual shed evolutionarily distinct HSV-1 strains on two occasions. The first strain was classified as a recombinant and the other strain clustered in clade A. High replication rates of different strains in the same person may facilitate the creation of recombinant clinical HSV-1 strains.

It was recently shown that the transcription factor T-bet is crucial for adequate innate and acquired immune responses to genital herpes simplex virus type 2 (HSV-2) infection in mice. To test the possible genetic influence of variations in the TBX21 gene encoding T-bet on susceptibility to infection, this study evaluated the frequencies of five different single-nucleotide polymorphisms (SNPs) in the human TBX21 gene in 159 HSV-2-infected individuals and compared them with those in 186 healthy HSV-2-seronegative controls. The data showed that one variation (rs17244587) in the 3'-untranslated region of TBX21 was strongly associated with the incidence of genital HSV-2 infection. The frequency of the A allele at this position was 0.19 in the group of HSV-2-infected individuals compared with 0.05 in the group of uninfected controls (P=9.3x10(-8)). Furthermore, a homozygous AA genotype was found only among HSV-2-infected individuals and not in seronegative controls. These results indicate that the host genetic background may affect susceptibility to HSV-2 infection in humans, with TBX21 as a strong candidate gene.

Background: Herpes simplex virus type 1 (HSV-1) infections are commonly acquired in childhood, asymptomatically or as a symptomatic infection. However, little is known about the time of HSV seroconversion during infancy and early childhood., Objective: To investigate the acquisition of IgG-antibodies to HSV in infants and children., Study Design: A longitudinal study, using type-specific HSV-1 and herpes simplex virus type 2 (HSV-2) enzyme-linked immunosorbent assays on sera collected from the mother and from their child at the age of 3, 5, 6, 12, 13 and 30 months., Results: The maternal seroprevalences for HSV-1 was 65% and for HSV-2 19%. A gradual loss of maternal antibodies was seen, with few infants having detectable HSV-1 antibodies at the age of 1 year. A more rapid decline was registered for HSV-2 antibodies. A small number of new HSV-1 infections occurred in 3-5-month olds and more than half of the new infections were detected before the age of 13 months. At the age of 30 months, 30% of the children were HSV-1 antibody positive., Conclusion: Seroconversion to HSV-1 commonly occurs already during infancy, suggesting that HSV-1 is transmitted primarily from parent to child.

Glycoprotein G-1 (gG-1) of herpes simplex virus type 1 (HSV-1) and gG-2 of HSV-2 are the only known HSV proteins that induce type-specific human antibody responses. Recently, it was shown that purified human anti-gG-1 and anti-gG-2 antibodies presented a type-specific reactivity to immunogenic stretches with high similarity between gG-1 and gG-2. In this study, the molecular basis for this type-specific recognition was investigated employing synthetic peptides covering the indicated regions, including substitutions of the type-specific residues. The results revealed that single or dual type-specific residues localized within regions of high similarity could induce significant structural differences, explaining the type-specific recognition of the human antibody response to the gG proteins.

The majority of herpes simplex virus type 2 (HSV-2) genital infections are asymptomatic. We wanted to evaluate the acceptance of HSV-2 antibody testing among people attending an STD clinic and to estimate, after counselling, the percentage of recognized and unrecognized HSV-2 infections. First visitors to an STD clinic were invited to participate by answering a questionnaire and taking a blood test for HSV-2 antibodies. HSV-2 seropositive individuals, who were unaware of having genital herpes, were offered an HSV-2 counselling visit and follow-up. Of 1769 patients offered testing, 57% accepted. Of 152 (15%) HSV-2 seropositive individuals, 41% had a self-reported history of genital herpes, approximately 30% had genital symptoms and 30% had no genital symptoms. The percentage of patients reporting genital symptoms was much higher in HSV-2 seropositives (45%) without a history of genital herpes than in an HSV-2 seronegative group (28%). HSV-2 antibody testing should be performed generously in all cases of uncharacteristic genital symptoms.

T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4(+) T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals responded in vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4(+) T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4(+) T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.

The changing spectrum of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infections makes it important to define the seroepidemiology of HSV. The object of this study was to determine the prevalence of HSV-1 and HSV-2 immunoglobulin G antibodies in a young Swedish population by investigating 2106 serum samples from people aged 0-19 y. Sera were tested in HSV type-specific enzyme-linked immunosorbent assays using glycoprotein G-1 (gG-1) and glycoprotein G-2 (gG-2) as antigens. The overall seroprevalence was 31% (95% CI 29-33) for HSV-1 and 0.5% (95% CI 0.2-0.9) for HSV-2. The HSV-1 seroprevalence was higher with increasing age, and significantly higher in the age cohort 15-19 y compared with 1-4-y-olds (37% vs 24%). The HSV-1 infection seemed to be acquired early in life. In the age cohort 1-2 y, the prevalence was over 20%, presumably reflecting an established viral infection. In adolescence the HSV-1 seroprevalence may reflect both oral and sexual transmission. The seroprevalence in the oldest age cohort did not differ significantly from that seen in a Swedish study in which sera were sampled from young girls in the 1970s.

Herpes simplex virus type 1 (HSV-1) encodes 11 envelope glycoproteins, of which glycoprotein G-1 (gG-1) induces a type-specific antibody response. Variability of the gG-1 gene among wild-type strains may be a factor of importance for a reliable serodiagnosis and typing of HSV-1 isolates. Here, we used a gG-1 type-specific monoclonal antibody (MAb) to screen for mutations in the immunodominant region of this protein in 108 clinical HSV-1 isolates. Of these, 42 isolates showed no reactivity to the anti-gG-1 MAb. One hundred five strains were further examined by DNA sequencing of the middle part of the gG-1 gene, encompassing 106 amino acids including the immunodominant region and epitope of the anti-gG-1 MAb. By phylogenetic comparisons based on the sequence data, we observed two (main) genetic variants of the gG-1 gene among the clinical isolates corresponding to reactivity or nonreactivity to the anti-gG-1 MAb. Furthermore, four strains appeared to be recombinants of the two gG-1 variants. In addition, one strain displayed a gG-1-negative phenotype due to a frameshift mutation, in the form of insertion of a cytosine nucleotide. When immunoglobulin G reactivity to HSV-1 in sera from patients infected with either of the two variants was investigated, no significant differences were found between the two groups, either in a type-common enzyme-linked immunosorbent assay (ELISA) or in a type-specific gG-1 antigen-based ELISA. Despite the here-documented existence of two variants of the gG-1 gene affecting the immunodominant region of the protein, other circumstances, such as early phase of infection, might be sought for explaining the seronegativity to gG-1 commonly found in a proportion of the HSV-1-infected patients.

Herpes simplex virus type 1 (HSV-1) has been associated with orofacial infections and HSV type 2 (HSV-2) with genital infections. This tropism of the virus seems to have changed and in clinical reports an increasing number of genital herpes infections caused by HSV-1 have been recognized. The aim of this study was to estimate the proportion of HSV-1 and HSV-2, respectively, among isolates from different anatomical sites typed in our laboratory during the years 1994-1998. Out of a total of 3,085 anogenital isolates, 29% were typed as HSV-1 and 71% as HSV-2. The highest prevalence of HSV-1 was registered among isolates from young women. Of 631 orofacial isolates, 4% were typed as HSV-2 and 96% as HSV-1. Of 69 finger/hand isolates, 54% were typed as HSV-1 and 46% as HSV-2, and of 95 isolates from other regions (abdomen, foot, etc.), 60% were typed as HSV-1 and 40% as HSV-2. It was found that HSV-2 was as common as HSV-1 in the extra-genital regions with the exception of the orofacial area, in which HSV-2 was seldom detected. Furthermore, the study showed an increasing proportion of HSV-1 among anogenital isolates during the study period. Taken together, these results suggest that a clear HSV type-related tropism might be limited to the permissiveness of the orofacial region for HSV-1, and that both serotypes may readily establish infections below the neck.

In a cross-sectional study, the occurrence of a self-reported history of labial herpes was evaluated. The study population comprised a stratified random sample of 5,000 individuals, aged 0-60 y, from south-west Sweden. A questionnaire, together with written and photographic descriptions of labial herpes lesions, was sent to the participants. Of 5,000 questionnaires sent out, 3597 (72%) were returned. In answer to the question "Have you ever had herpes?" the point estimate was 26.6% (95% confidence interval [CI] 25.1%-28.1%) and for the question "Have you had herpes in the last 2 y?" it was 19.4 (95% CI 18.0-20.8). The proportion of individuals who had had herpes was higher for the older age groups. About 5% of children aged < or = 5 y had experienced labial herpes. Herpes was more frequently reported by females than males: odds ratio 1.29 (95% CI 1.10-1.51). Compared to previous studies in Sweden, our data do not indicate that the occurrence of labial herpes lesions has decreased.

Serological diagnosis of herpes simplex virus (HSV) infections requires assays based on antigens that expose type-specific determinants. This study was designed to outline the B-cell epitopes of the type-specific glycoprotein G-1 (gG-1) of HSV type 1 (HSV-1), by investigating the reactivity of human anti-gG-1 antibodies, purified from 21 HSV-1-isolation-proven patient sera, to cellulose-bound synthetic peptides spanning the entire gG-1 sequence. The epitope mapping demonstrated that these antibodies bound preferentially to antigenic determinants that localized to regions with a high degree of amino acid similarity to the corresponding glycoprotein in HSV-2, gG-2. In spite of this, the purified anti-gG-1 antibodies were found to be non-reactive to native gG-2 antigen, as well as to overlapping gG-2 peptides, thus supporting the role of gG-1 as a prototype HSV-1 type-specific antigen. One immunodominant region, delimited by amino acids 112-127, reacted with all purified anti-gG-1 antibodies and may be of interest for the further development of a peptide-based HSV-1 type-specific seroassay.

Glycoprotein G (gG) of herpes simplex virus type 1 (HSV-1) has been used as a prototype antigen for HSV-1 type-specific serodiagnosis, but data on the sequence variability of the gene coding for this protein in wild-type strains are lacking. In this study, direct DNA sequencing of the gG-1 genes from PCR products was performed with clinical HSV-1 isolates from 11 subjects as well as with strains Syn 17(+), F, and KOS 321. The reference strains Syn 17(+) and F showed a high degree of conservation, while KOS 321 carried 13 missense mutations and, in addition, 12 silent mutations. Three clinical isolates showed mutations leading to amino acid alterations: one had a mutation of K(122) to N, which is a gG-1-to-gG-2 alteration; another contained all mutations which were observed in KOS 321 except two silent mutations; and the third isolate carried five missense mutations. Two clinical isolates as well as strain KOS 321 showed a mutation (F(111)-->V) within the epitope of a gG-1-reactive monoclonal antibody (MAb). When all viruses were tested for reactivity with the anti-gG-1 MAb, the three strains with the F(111)-->V mutation were found to be unreactive. Furthermore, gG-1 antibodies purified from sera from the two patients carrying strains mutated in this epitope were less reactive when they were tested by an HSV-1-infected-cell assay. Therefore, our finding that the sequence variability of the gG-1 gene also affects B-cell epitope regions of this protein in clinical isolates may have consequences for the use of this protein as a type-specific antigen for serodiagnosis.