Primary Herpes Simplex Research Articles

T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.

Concomitant Primary Labial and Genital Herpes Simplex I Infections

Abstract There has been a decrease in the prevalence of herpes simplex type I (HSV I) infection in adolescents in the United States while the relative number of genital infections caused by HSV I has increased. Although transmission is more likely to occur during active skin lesions, asymptomatic shedding of herpes simplex virus from oral or genital sources can lead to infection in susceptible hosts. I wish to report the acquisition of concomitant primary labial and genital HSV I infection in a man and woman from an asymptomatic woman with a history of labial HSV I infection.

Characterization of Herpes Simplex Virus Infections Seen in the Pediatric Dermatology Office.

Atypical and severe clinical manifestations of primary and recurrent herpes simplex virus (HSV) infections may present to a pediatric dermatologist for evaluation. The purpose of this study was to characterize the clinical features of the population diagnosed with HSV referred to a pediatric dermatology office. This retrospective case series examined patients diagnosed with HSV in a pediatric dermatology practice at an academic medical center from 2005 to 2015. Characteristics of the population were collected and analyzed. In this study of 48 children diagnosed with HSV, 33% presented at age 2 years or younger, with approximately half having exhibited initial symptoms before 2 years of age; 39.6% of the population had six or more outbreaks per year. The outbreaks were equally divided between unifocal and multifocal presentations, with 60% of children without any labial or mucosal involvement. Suppressive treatment was initiated in 33% of patients; the average age at initiation was 6 years. Our data characterize a subset of immunocompetent young children who present to pediatric dermatologists with frequent HSV outbreaks that are often multifocal and involve cutaneous sites, with or without mucosal involvement.

Management of herpes labialis triggered by emotional stress

Background: Herpes labialis is a form of secondary or recurrence of primary herpes simplex infection. Herpes simplex virus is latent. It can reactivate due to reactivation of the virus induced by emotional stress, high fever, ultraviolet exposed, oral mucosal or nerve tissue trauma, immunosuppression condition, and hormonal disorders. Purpose: The study aimed to report the management of patients with herpes labialis on the lower lip triggered by emotional stress. Case: A 58 year-old woman complained of pain in her lower lip. The patient had suffered from the pain since one month ago. The patient had been treated with a lip ointment, triamcinolone acetonid 0.1% (Kenalog®), for 2 weeks, but became thick, dry, and worse. She said that she got many calamities related to her family, leading to the increased busyness and psychologically distressed conditions. Extra oral examination of the lower lip showed erythematous erosion sized 4x4 mm, yellowish red crusting sized 3x4 mm, and translucent multiple vesicles sized 1x1 mm with well circumscribed as well as irregular edges. On palpation submandibular lymph nodes, dextra and sinistra were palpable, rubbery, mobile and painless. Based on intra-oral examination, however, there were no abnormalities. Case management: The diagnosis was determined based on anamnesis, clinical examinations, and supporting examination of Ig M and anti HSV-1 Ig G. The patient then was prescribed systemic and topical Acyclovir. Conclusion: Some laboratory tests are necessary to confirm the diagnosis and determine the accurate therapy of herpes labialis in addition to the history and clinical features.

P180 An unusual cause of pharyngo-tonsillar ulceration

Background/introduction Herpes Simplex 1 virus has historically been known to cause oral and genital symptoms, whereas Herpes Simplex 2 virus is mostly associated with genital symptoms. We present the first case in the UK, to our knowledge, of primary Herpes Simplex 2 virus causing genital and pharyngo-tonsillar ulceration in a sexually active female patient. Case A 33 year old female patient attended the GUM clinic reporting 2 day history of genital sores associated with dysuria. She has recently completed a 3 day course of Nitrofurantoin for presumed UTI with no effect, and is currently taking a course of Penicillin for tonsillitis. She has a new male partner of 1 month duration. Genital examination revealed bilateral inguinal lymphadenopathy with multiple herpetic lesions on the labia majora and minora. Pharyngeal examination revealed pustular looking tonsils with ulceration bilaterally, more marked on the left. Cervical chain lymphadenopathy was also present. HSV PCR swabs taken from both the tonsillar and genital ulcers came back positive for HSV-2. She was initially treated with a 10 day course of Aciclovir and returned for follow up 1 week later. Repeat examination revealed fully healed vulval ulcers and normal tonsillar appearance. Discussion/conclusion This is the first UK reported case of primary HSV-2 causing pharyngo-tonsillar ulceration in addition to genital symptoms. The patient made a full and rapid recovery following prompt treatment with Aciclovir. This case highlights the importance of recognising less common causes for tonsillitis such as HSV-2, which responds very quickly to antiviral treatment.

Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH

Herpesviral pathogenesis stems from infection of multiple cell types including the site of latency and cells that support lytic replication. Herpesviruses utilize distinct cellular pathways, including low pH endocytic pathways, to enter different pathophysiologically relevant target cells. This review details the impact of the mildly acidic milieu of endosomes on the entry of herpesviruses, with particular emphasis on herpes simplex virus 1 (HSV-1). Epithelial cells, the portal of primary HSV-1 infection, support entry via low pH endocytosis mechanisms. Mildly acidic pH triggers reversible conformational changes in the HSV-1 class III fusion protein glycoprotein B (gB). In vitro treatment of herpes simplex virions with a similar pH range inactivates infectivity, likely by prematurely activating the viral entry machinery in the absence of a target membrane. How a given herpesvirus mediates both low pH and pH-independent entry events is a key unresolved question.

Vaccination with the Secreted Glycoprotein G of Herpes Simplex Virus 2 Induces Protective Immunity after Genital Infection.

Herpes simplex virus 2 (HSV-2) infects the genital mucosa and establishes a life-long infection in sensory ganglia. After primary infection HSV-2 may reactivate causing recurrent genital ulcerations. HSV-2 infection is prevalent, and globally more than 400 million individuals are infected. As clinical trials have failed to show protection against HSV-2 infection, new vaccine candidates are warranted. The secreted glycoprotein G (sgG-2) of HSV-2 was evaluated as a prophylactic vaccine in mice using two different immunization and adjuvant protocols. The protocol with three intramuscular immunizations combining sgG-2 with cytosine-phosphate-guanine dinucleotide (CpG) motifs and alum induced almost complete protection from genital and systemic disease after intra-vaginal challenge with HSV-2. Robust immunoglobulin G (IgG) antibody titers were detected with no neutralization activity. Purified splenic CD4+ T cells proliferated and produced interferon-γ (IFN-γ) when re-stimulated with the antigen in vitro. sgG-2 + adjuvant intra-muscularly immunized mice showed a significant reduction of infectious HSV-2 and increased IFN-γ levels in vaginal washes. The HSV-2 DNA copy numbers were significantly reduced in dorsal root ganglia, spinal cord, and in serum at day six or day 21 post challenge. We show that a sgG-2 based vaccine is highly effective and can be considered as a novel candidate in the development of a prophylactic vaccine against HSV-2 infection.

Topical Administration Is a Promising Inoculating Route versus Intramuscular Inoculation for the Nanoparticle-Carried DNA Vaccine to Prevent Corneal Infections

Purpose: To evaluate the comparative effect of topical versus intramuscular administration of nanoparticle-carried DNA vaccine in preventing corneal herpes simplex virus type 1 (HSV-1) infection. Methods: Nanoparticle [polyethylenimine (PEI)-Fe₃O₄]-carried DNA vaccine (PEI-Fe₃O₄-pRSC-gD-IL-21) or DNA vaccine (pRSC-gD-IL-21) alone were topically versus intramuscularly inoculated into one eye each of mice on days 0, 14 and 28. Three weeks after the final immunization, the specific immune responses and clinical degrees of primary herpes simplex keratitis were evaluated. Results: Topical inoculation of nanoparticle-carried DNA vaccine induced mice to generate similar levels of specific HSV-1-neutralizing antibody, IFN-γ and IL-4 in serum and specific killing (cytotoxicity) and proliferative activities of the splenic lymphocytes, but a significantly higher level of secretory IgA in tears compared to those of intramuscular inoculation. More importantly, the mice inoculated topically showed a significantly decreased herpes simplex keratitis severity than the mice inoculated intramuscularly after HSV-1 challenge on the corneas of the mice. Conclusions: Topical inoculation of nanoparticle-carried DNA vaccine elicits a stronger specific local immune response and more effectively inhibits herpes simplex keratitis as compared to intramuscular inoculation in an HSV-1 ocular challenge mouse model. Thus, topical administration may be a promising inoculating route for the nanoparticle-carried DNA vaccine to prevent corneal infections.

A Dual Role for Corneal Dendritic Cells in Herpes Simplex Keratitis: Local Suppression of Corneal Damage and Promotion of Systemic Viral Dissemination.

The cornea is the shield to the foreign world and thus, a primary site for peripheral infections. However, transparency and vision are incompatible with inflammation and scarring that may result from infections. Thus, the cornea is required to perform a delicate balance between fighting infections and preserving vision. To date, little is known about the specific role of antigen-presenting cells in viral keratitis. In this study, utilizing an established murine model of primary acute herpes simplex virus (HSV)-1 keratitis, we demonstrate that primary HSV keratitis results in increased conventional dendritic cells (cDCs) and macrophages within 24 hours after infection. Local depletion of cDCs in CD11c-DTR mice by subconjuntival diphtheria toxin injections, led to increased viral proliferation, and influx of inflammatory cells, resulting in increased scarring and clinical keratitis. In addition, while HSV infection resulted in significant corneal nerve destruction, local depletion of cDCs resulted in a much more severe loss of corneal nerves. Further, local cDC depletion resulted in decreased corneal nerve infection, and subsequently decreased and delayed systemic viral transmission in the trigeminal ganglion and draining lymph node, resulting in decreased mortality of mice. In contrast, sham depletion or depletion of macrophages through local injection of clodronate liposomes had neither a significant impact on the cornea, nor an effect on systemic viral transmission. In conclusion, we demonstrate that corneal cDCs may play a primary role in local corneal defense during viral keratitis and preserve vision, at the cost of inducing systemic viral dissemination, leading to increased mortality.

P04.07 “Summer loving”: an analysis of seasonal differences in sexual behaviour and sexually transmissible infections

Introduction Public health campaigns must be timed to target their audience at times of highest risk. To date no study has correlated seasonal differences in sexual behaviour with those in sexually transmissible infection (STI) positivity; and no seasonal study has been conducted in the southern hemisphere. Our study aimed to describe seasonal differences in sexual behaviour and correlate this with STI positivity. Methods This was a cross-sectional study of individuals attending the Melbourne Sexual Health Centre (MSHC) over a 9 year period from 2006–2014 inclusive. We conducted separate analyses for women, men who have sex with men (MSM) and men who have sex with women (MSW). Seasonal patterns of sexual behaviour (partner numbers, condom use and injecting drug use), and STI positivity were examined in all groups. STI with a high symptomatic rate and short incubation period were selected for the analysis: gonorrhoea, primary herpes simplex virus (HSV) infections, non-gonococcal urethritis (NGU) (men only), and pelvic inflammatory disease (PID) (women only). Results All groups reported a significantly higher number of partners in summer compared to winter (women P MSW reported less consistent condom use in summer (P = 0.016); a similar but non-significant trend was observed in MSM and women. The urethral gonorrhoea positivity among MSM was significantly higher in summer compared to winter (P = 0.017). Similarly, the NGU positivity among MSW was the highest in summer (P = 0.009). In women PID diagnoses climbed over summer to peak in autumn, which then dropped to a low in winter (P = 0.025). The other STIs did not show statistically significant seasonal differences. Conclusion Our study describes a peak in sexual partner number and STI positivity in summer. This seasonal difference must inform the timing of public health campaigns, as these are likely to be maximally effective in spring and summer. Disclosure of interest statement None.

Primary oropharyngeal herpes simplex virus infection in adults: a profile of thirty-two immunoserologically confirmed cases.

Primary oropharyngeal herpes simplex virus infection in adults: a profile of thirty-two immunoserologically confirmed cases.

Disseminated Primary Herpes Simplex Virus Type 2 Infection in a 22-Year-Old male.

We present a case of primary disseminated herpes simplex virus type 2 (HSV-2) cutaneous disease in a 22-year-old male. We discuss the immune response to HSV-2 infection as well as the extragenital manifestations of HSV-2 observed in immune-competent and immune-suppressed persons.

Severe disseminated primary herpes simplex infection as skin manifestation in GATA2 deficiency

Severe disseminated primary herpes simplex infection as skin manifestation in GATA2 deficiency

Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency.

DOCK8 deficiency in humans and mice leads to multiple defects in immune cell numbers and function. Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic, cutaneous viral infections, including those caused by herpes simplex virus (HSV). The underlying mechanism of the specific susceptibility to these chronic cutaneous viral infections is currently unknown, largely because the effect of DOCK8-deficiency has not been studied in suitable models. A better understanding of these mechanisms is required to underpin the development of more specific therapies. Here we show that DOCK8 deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads. Furthermore, DOCK8-deficient mice showed a lack of CD4+ T cell infiltration into HSV-infected skin.

Novel rat models to study primary genital herpes simplex virus-2 infection.

In this study we describe that six rat models (SD, WIST, LEW, BN, F344 and DA) are susceptible to intravaginal herpes simplex virus-2 (HSV-2) infection after pre-treatment with progesterone. At a virus dose of 5×10(6) PFU of HSV-2, all rat models were infected presenting anti-HSV-2 antibodies, infectious virus in vaginal washes, and HSV-2 DNA genome copies in lumbosacral dorsal root ganglia and the spinal cord. Most of the LEW, BN, F344, and DA rats succumbed in systemic progressive symptoms at day 8-14 post infection, but presented no or mild genital inflammation while SD and WIST rats were mostly infected asymptomatically. Infected SD rats did not reactivate HSV-2 spontaneously or after cortisone treatment. In an HSV-2 virus dose reduction study, F344 rats were shown to be most susceptible. We also investigated whether an attenuated HSV-1 strain (KOS321) given intravaginally, could protect from a subsequent HSV-2 infection. All LEW, BN, and F344 rats survived a primary HSV-1 infection and no neuronal infection was established. In BN and F344 rats, anti-HSV-1 antibodies were readily detected while LEW rats were seronegative. In contrast to naïve LEW, BN, and F344 rats where only 3 of 18 animals survived 5×10(6) PFU of HSV-2, 23 of 25 previously HSV-1 infected rats survived a challenge with HSV-2. The described models provide a new approach to investigate protective effects of anti-viral microbicides and vaccine candidates, as well as to study asymptomatic primary genital HSV-2 infection.

Primary Genital Herpes Simplex Virus Type I in Preterm Prelabour Rupture of Membranes at 30 Weeks' Gestation.

Background. Disseminated herpes simplex virus (HSV) in the neonate is associated with significant morbidity and mortality. Current guidelines recommend caesarean in third-trimester maternal primary genital HSV outbreaks to prevent transmission from mother to fetus. In the premature fetus, however, expectant management is often necessary to reduce morbidity of prematurity. The benefit of performing caesarean after 6 hrs of rupture of membranes (ROM) to reduce maternal-fetal transmission is unclear. Case. A female patient with primary genital HSV type 1 outbreak coinciding with preterm, prelabour rupture of membranes (PPROM) at 30 + 3 weeks' gestation. An immediate caesarean section was not performed after multidisciplinary team discussion due to the benefits of glucocorticoids on immune complications of prematurity. The patient had expectant management for 5 days with intravenous (IV) aciclovir and then delivered an infant vaginally with disseminated neonatal HSV. Conclusion. We address the rare presentation of primary HSV infection associated with PPROM and the dilemma of how to manage these patients given the limited literature. We discuss the role of intrauterine compartment monitoring with amniocentesis, the mode of delivery when ROM has occurred for 120 hours, expectant management to reduce prematurity, and the effectiveness of aciclovir to reduce viral shedding in the prevention of neonatal HSV.

Valaciclovir versus aciclovir for the treatment of primary genital herpes simplex: a cost analysis.

The current guidelines for the treatment of primary herpes simplex in the Genito-urinary department in Sheffield Teaching Hospitals NHS Foundation Trust, recommend valaciclovir as a first-line medication. This is a prodrug of aciclovir, which has been used for many years as a treatment for primary herpes simplex virus. The basis of the recommendation largely relates to valaciclovir being more bioavailable than aciclovir. However, there is no evidence to suggest this has an effect on overall outcome with regard to symptom control and viral shedding. The purpose of the service evaluation was to discover if significant cost savings could be made by changing the prescribing policy to make aciclovir the drug of choice for primary herpes simplex virus. Based on 160 patients receiving valaciclovir (500 mg BD) during April 2013 and March 2014, if they had been treated with aciclovir (400 mg TDS) instead, a saving of £828.80 (66% reduction) could have been made.

The role of dendritic cells in immunity against primary herpes simplex virus infections

Herpes simplex virus (HSV) is a DNA virus with tropism for infecting skin and mucosal epithelia during the lytic stages of its complex life cycle. The immune system has evolved a multitude of strategies to respond to primary HSV infections. These include rapid innate immune responses largely driven by pattern recognition systems and protective anti-viral immunity. Dendritic cells (DC) represent a versatile and heterogenic group of antigen presenting cells that are important for pathogen recognition at sites of infection and for priming of protective HSV-specific T cells. Here we will review the current knowledge on the role of DCs in the host immune response to primary HSV infection. We will discuss how DCs integrate viral cues into effective innate immune responses, will dissect how HSV infection of DCs interferes with their capacity to migrate from sites of infection to the draining lymph nodes and will outline how migratory DCs can make antigens available to lymph node resident DCs. The role of distinct DC subsets and their relevant contribution to antigen presentation on MHC class I and MHC class II molecules will be detailed in the context of T cell priming in the lymph node and the elicitation of effector function in infected tissues. An improved understanding of the fundamental mechanisms of how DCs recognize HSV, process and present its antigens to naïve and effector T cells will not only assist in the improvement of vaccine-based preventions of this important viral disease, but also serves as a paradigm to resolve basic immunological principles.

Topical herpes simplex virus 2 (HSV-2) vaccination with human papillomavirus vectors expressing gB/gD ectodomains induces genital-tissue-resident memory CD8+ T cells and reduces genital disease and viral shedding after HSV-2 challenge.

No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8(+) T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8(+) T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. Genital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.

Expression, Inducers and Cellular Sources of the Chemokine MIG (CXCL 9), During Primary Herpes Simplex Virus Type-1 Infection of the Cornea

Purpose: To investigate the production of monokine induced by gamma-interferon (MIG) during a primary Herpes simplex virus type 1 (HSV-1) infection of the cornea. We hypothesize that multiple CXCR3 ligands are involved in T cell recruitment during HSV-1 corneal infection and that neutrophils have the potential to contribute to their production.Materials and methods: Levels of MIG were evaluated in an in vivo murine model of HSV-1 corneal infection by quantitative ELISA. Cultured murine corneal fibroblast (MCF) cells and purified neutrophils were stimulated in vitro with IFN-γ and IL-1α to determine inducers of MIG. Cellular sources of MIG production in vivo were investigated via cellular depletion studies. Additionally, MIG production resulting from interaction between resident human corneal cells and neutrophils was evaluated in an ex vivo model of human corneal infection.Results: MIG was significantly elevated on days 2–6 and on day 8 following corneal infection. MCF and neutrophils secreted MIG in response to IFN-γ, but not IL-1α stimulation. Co-stimulation with IFN-γ and IL-1α induced a four-fold increase in MIG production by MCF. However, the same combination led to a three-fold decrease in MIG production by neutrophils. In vivo, a 52% reduction in MIG levels was observed in the neutrophil depleted host. In the human ex vivo model, MIG levels were significantly elevated in response to communication between HSV-1 infected corneal tissue and neutrophils.Conclusions: Here, we report the evidence for the production of MIG, a second CXCR3 ligand, during the primary immune response to HSV-1 corneal infection. Our results support the hypothesis that both neutrophils and resident corneal cells contribute to MIG production in vivo. However, neutrophils produce MIG in response to communication with HSV-1-infected resident corneal cells more efficiently than by direct interaction with virus. In addition, we found that MIG production by neutrophils and resident corneal cells was differentially regulated by IL-1α.