Herpes Simplex Virus Reactivation Research Articles

An Inquiry into the Molecular Basis of HSV Latency and Reactivation

Herpes simplex virus (HSV) evolved an elegant strategy that enables the virus to impact a large fraction of the human population. The virus replicates at the portal of entry (mouth, genitals) and concurrently it is transported retrograde to sensory neurons. In sensory neurons it establishes a silent (latent) infection. A variety of stimuli can reactivate the virus. The reactivated virus is transmitted anterograde to a site at the portal of entry for transmission by physical contact between infected and uninfected tissues to other individuals. The central issue is how a virus that vigorously replicates and successfully blocks the innate immune defenses of the host at the portal of entry into the body remains silent in sensory neurons. The presentation focuses on three key issues: (a) current assessment of the impact of HSV on human health, (b) the mechanisms by which the virus overcomes a key host defense mechanism at the portal of entry into the body and yet is silenced in latently infected neurons, and (c) the mechanisms by which the virus reactivates.

Acyclovir in aesthetic practice: mechanisms of action, medical uses and precautions

Antiviral medications are used to treat viral infections such as herpes simplex virus, hepatitis B and human immunoficiency virus (HIV). Antivirals do not destroy their target pathogen; instead, they inhibit their development. Acyclovir was the first effective antiviral used for the herpes simplex and varicella-zoster viruses. Whereas the herpes simplex virus is known to cause mouth ulcers, cold sores, conjunctivitis, mouth ulcers and genital herpes, the varicella-zoster virus causes shingles and chickenpox. A herpes simplex reaction can be triggered by trauma, surgery and cosmetic interventions such as dermal fillers, chemical peels, micro-needling and laser procedures. The soft tissue damage caused by penetration of the skin in dermal fillers is sufficient to trigger the virus in susceptible patients. Although no large trials or studies have been carried out, it is widely accepted that when prophylactically administered, acyclovir can reduce the risk of herpes simplex virus reactivation.

Relapsed Herpes Simplex Virus Encephalitis after Epilepsy Surgery

Relapsed herpes simplex virus (HSV) encephalitis after neurosurgery is a very rare condition. An 11-year-old boy suffered from relapsed HSV encephalitis five days after neurosurgery to remove the epileptogenic focus six years after prior HSV encephalitis. He was diagnosed with HSV encephalitis reactivation after positive HSV polymerase chain reaction results following a lumbar puncture, and this diagnosis was supported by consistent radiologic and histopathologic findings. Moreover, focal cortical dysplasia coexisted with inflammatory changes resulting from a viral infection based upon the removed brain tissue. This case may support the hypothesis that neurosurgery may be a triggering factor of HSV reactivation.

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSV expresses a long noncoding RNA and a set of microRNAs, but viral proteins are not expressed. The mechanism by which latent HSV reactivates is unknown. A key question is, what is the mechanism of reactivation in the absence of tegument proteins that enable gene expression in productive infection? Elsewhere we have reported the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to NGF or delayed reactivation in medium containing NGF and EGF. We also reported that in the ganglionic organ cultures incubated in medium containing antibody to NGF, all viral genes are derepressed at once without requiring de novo protein synthesis within the time frame of a single replicative cycle. Here we report that latent HSV in ganglia immersed in medium containing NGF and EGF is reactivated by (i) broad spectrum as well as specific histone deacetylase 1 or histone deacetylase 4 inhibitors, (ii) activation of p300/CBP, and (iii) either STAT3 carrying the substitution of tyrosine 705 to phenylalanine or an inhibitor of STAT3. Conversely, reactivation of latent HSV was blocked by p300/CBP inhibitor in medium containing antibody to NGF. The results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation.

Longitudinal study on oral shedding of herpes simplex virus 1 and varicella‐zoster virus in individuals infected with HIV

Primary herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) infection leads to a life-long latent infection of ganglia innervating the oral mucosa. HSV-1 and VZV reactivation is more common in immunocompromised individuals and may result in viral shedding in saliva. We determined the kinetics and quantity of oral HSV-1 and VZV shedding in HSV-1 and VZV seropositive individuals infected with HIV and to assess whether HSV-1 shedding involves reactivation of the same strain intra-individually. HSV-1 and VZV shedding was determined by real-time PCR of sequential daily oral swabs (n = 715) collected for a median period of 31 days from 22 individuals infected with HIV. HSV-1 was genotyped by sequencing the viral thymidine kinase gene. Herpesvirus shedding was detected in 18 of 22 participants. Shedding of HSV-1 occurred frequently, on 14.3% of days, whereas solely VZV shedding was very rare. Two participants shed VZV. The median HSV-1 load was higher compared to VZV. HSV-1 DNA positive swabs clustered into 34 shedding episodes with a median duration of 2 days. The prevalence, duration and viral load of herpesvirus shedding did not correlate with CD4 counts and HIV load. The genotypes of the HSV-1 viruses shed were identical between and within shedding episodes of the same person, but were different between individuals. One-third of the individuals shed an HSV-1 strain potentially refractory to acyclovir therapy. Compared to HSV-1, oral VZV shedding is rare in individuals infected with HIV. Recurrent oral HSV-1 shedding is likely due to reactivation of the same latent HSV-1 strain.

Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection

SummaryMost herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown CD8+ T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ), the portal of neuronal release of reactivating virus, for prolonged time periods after lesions are cleared1,2. The phenotype and function of this persistent CD8+ T-cell population remain unknown. Here, using cell type-specific laser capture microdissection, transcriptional profiling and T-cell receptor beta (TCRβ) genotyping on sequential genital skin biopsies, we show CD8αα+ T cells are the dominant resident population of DEJ CD8+ T cells that persist at the site of prior HSV-2 reactivation. CD8αα+ T cells located at the DEJ lack chemokine receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCRβ chain repertoire revealed that the DEJ CD8αα+ T cells are oligoclonal with diverse usage of TCR VB genes, which differ from those commonly described for MAIT and NKT cells. Dominant clonotypes overlapped among multiple recurrence episodes over a period of two and a half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8αα+ T cells. These studies indicate DEJ CD8αα+ T cells are tissue resident cells that appear to play a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα+ T cells might be a critical component for developing effective vaccines against skin and mucosal infections.

Herpes simplex virus reactivation and dental procedures

Dental extraction is reported to trigger recurrent herpes labialis (RHL). This aims to prospectively study the clinical occurrence of RHL and the oral herpes simplex virus type 1 (HSV-1) viral shedding before and 3 days after different dental procedures. Oral HSV-1 DNA was measured by real-time PCR before and 3 days after dental procedures of the inferior dentition in 57 immunocompetent patients (mean age 32.4 years) who were selected and divided into four distinct subgroups (dental inspection without anesthesia, n = 19; dental filling under local anesthesia, n = 14; molar extraction under local anesthesia, n = 15; and molar extraction under general anesthesia, n = 9) and compared to 32 healthy controls (mean age 33 years). None of the patients suffered from RHL at day 3. Oral HSV-1 DNA was detected before and after procedure in 1.7 % (1/57) and 5.3 % (3/57), respectively [dental inspection without anesthesia, 5.3 % (1/19); molar extraction under local anesthesia, 6.7 % (1/15); and molar extraction under general anesthesia, 11 % (1/9)]. None of the controls presented RHL or detectable oral HSV-1 DNA. There was no statistically significant difference between the study groups and controls. Molar extraction increases the risk of oral HSV-1 shedding but not of RHL. Procedure-related nerve damage probably accounts for HSV reactivation. Antiviral prophylaxis for RHL is not routinely recommended for dental procedures, regardless of a prior history of RHL.

Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract

Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI:http://dx.doi.org/10.7554/eLife.00288.001.

VP16‐HCF interaction is required for herpes simplex virus exit from latency in neurons in vivo

A mechanistic understanding of viral and host functions regulating herpes simplex virus (HSV) latency and reactivation remains a major goal. We have shown that the interaction of VP16 and Oct‐1 is required very early during entry into the lytic cycle from the latent state and have proposed a VP16‐dependent model of reactivation in vivo. HCF‐1 has important roles in promoting HSV replication and a model has been proposed in which stress induces translocation of HCF‐1 into the neuronal nucleus and reactivation is regulated by direct recruitment of HCF to viral IE genes. To investigate whether HCF‐1 can precipitate viral gene expression in latently infected neurons in the absence of binding to VP16, a mutation in VP16 at Y364A, shown previously to disrupt VP16‐ HCF interaction (but not interaction with Oct‐1) was engineered into HSV‐1. Three independent isolates and a genomically restored virus were examined in vitro and in the mouse ocular model. Our findings demonstrate that the interaction of VP16 with HCF‐1 is required for efficient infection at low moi, efficient viral replication in vivo, and exit from latency/entry into the lytic cycle in trigeminal ganglion neurons in mice following hyperthermic stress. In the absence of VP16 binding, nuclear translocation of HCF is not sufficient to initiate the viral lytic cycle, demonstrating the key role of VP16 in regulating in vivo reactivation.

A Novel Selective LSD1/KDM1A Inhibitor Epigenetically Blocks Herpes Simplex Virus Lytic Replication and Reactivation from Latency

ABSTRACTCellular processes requiring access to the DNA genome are regulated by an overlay of epigenetic modifications, including histone modification and chromatin remodeling. Similar to the cellular host, many nuclear DNA viruses that depend upon the host cell’s transcriptional machinery are also subject to the regulatory impact of chromatin assembly and modification. Infection of cells with alphaherpesviruses (herpes simplex virus [HSV] and varicella-zoster virus [VZV]) results in the deposition of nucleosomes bearing repressive histone H3K9 methylation on the viral genome. This repressive state is modulated by the recruitment of a cellular coactivator complex containing the histone H3K9 demethylase LSD1 to the viral immediate-early (IE) gene promoters. Inhibition of the activity of this enzyme results in increased repressive chromatin assembly and suppression of viral gene expression during lytic infection as well as reactivation from latency in a mouse ganglion explant model. However, available small-molecule LSD1 inhibitors are not originally designed to inhibit LSD1, but rather monoamine oxidases (MAO) in general. Thus, their specificity for and potency to LSD1 is low. In this study, a novel specific LSD1 inhibitor was identified that potently repressed HSV IE gene expression, genome replication, and reactivation from latency. Importantly, the inhibitor also suppressed primary infection of HSV in vivo in a mouse model. Based on common control of a number of DNA viruses by epigenetic modulation, it was also demonstrated that this LSD1 inhibitor blocks initial gene expression of the human cytomegalovirus and adenovirus type 5.IMPORTANCE Epigenetic mechanisms, including histone modification and chromatin remodeling, play important regulatory roles in all cellular processes requiring access to the genome. These mechanisms are often altered in disease conditions, including various cancers, and thus represent novel targets for drugs. Similarly, many viral pathogens are regulated by an epigenetic overlay that determines the outcome of infection. Therefore, these epigenetic targets also represent novel antiviral targets. Here, a novel inhibitor was identified with high specificity and potency for the histone demethylase LSD1, a critical component of the herpes simplex virus (HSV) gene expression paradigm. This inhibitor was demonstrated to have potent antiviral potential in both cultured cells and animal models. Thus, in addition to clearly demonstrating the critical role of LSD1 in regulation of HSV infection, as well as other DNA viruses, the data extends the therapeutic potential of chromatin modulation inhibitors from the focused field of oncology to the arena of antiviral agents.

Herpes Simplex Encephalitis Occurring During Chemo-Radiotherapy in Nasopharyngeal Carcinoma – A Case Report from Saudi Arabia

Aim: To see possible association between the chemotherapy, radiotherapy or both with the reactivation of Herpes simplex virus 1(HSV1) in brain which merits further dialogue in the field of current evidence based literature. Presentation of Case: We present a case of 46 years old male patient who developed herpes simplex encephalitis (HSE) while receiving radical chemo-radiation for locally advanced nasopharyngeal carcinoma. Full informed consent was obtained for publication of this case. He was treated with protracted course of anti-virals and is currently leading a healthy life. Study Design: The study is a case report of a rare but important side effect of a common chemoradiation procedure. Place and Duration of Study: The study took place at Comprehensive Cancer Center, King Fahad Medical City. It was reported during June 2013. Discussion: HSV1 causes several disseminated primary infections including herpes labialis, gingivostomatitis, and corneal infections. It is particularly notorious for causing potentially fatal encephalitis. Its reactivation is linked to several environmental factors Case Study British Journal of Medicine & Medical Research, 3(4): 2299-2305, 2013 2300 including chemotherapy and radiotherapy. Conclusion: This case report emphasizes on the possible role of chemo-radiation as causation of this life threatening condition, its early detection, prompt and aggressive treatment.

Frequent Detection of Herpes Simplex Virus Antigen in Skin and Peripheral Blood CD34+ Mononuclear Cells from Patients with Graft-versus-Host Disease

Viruses are implicated in the initiation or flare of graft-versus-host disease (GVHD) by virtue of their ability to activate antigen-presenting dendritic cells (DC). Herpes simplex virus (HSV) infects circulating CD34+ stem cell progenitors, favoring their differentiation into skin homing DC (CD1a+ Langerhans cells) that contribute to the development of an inflammatory skin rash known as HSV-associated erythema multiforme (HAEM). Following on these findings, we conducted a prospective study to examine whether HSV is also associated with GVHD. Skin biopsies and peripheral blood mononuclear cells (PBMC) were collected from 37 consecutive patients on admission before and after allogeneic hematopoietic stem cell transplantation (HSCT) and examined for HSV antigen (Pol) expression and the presence of Pol+CD34+ and Pol+CD1a+ cells. Sixteen patients developed a skin rash that was histopathologically consistent with GVHD (group I), 3 patients had a rash that was not GVHD (group II, EM-like) and 18 patients did not develop any rash after HSCT (group III). Skin biopsies from the group I patients were Pol negative pre-HSCT (baseline) but became Pol+ after the diagnosis of GVHD. The GVHD biopsies also contained Pol+CD34+ and Pol+CD1a+ cells, and these patients had a significant percentage of circulating Pol+CD34+ and Pol+CD1a+ PBMC. By contrast, the group II patients had Pol+ skin cells and Pol+CD34+ circulating PBMC at baseline that decreased post-HSCT. The group III patients had Pol negative skin and very few circulating Pol+CD34+ and Pol+CD1a+ PBMC at baseline that were not significantly changed post-HSCT. The data associate skin GVHD with HSV reactivation during conditioning and its propensity for nonreplicative infection of CD34+ PBMC that induces DC activation. Further studies are needed to better elucidate this association.

Reactivation of Herpes Simplex Virus and Cytomegalovirus in a Case of Thymoma-associated Graft-versus-host Disease-like Erythroderma

a 64-year-old woman with a 4-year history of pruritic erythema was admitted to our hospital because of aggravation of the erythema that did not respond to 20 mg/ day oral prednisolone. The patient had had malignant thymoma and myasthenia gravis for 12 years, together with recurrent oral herpes infection for several years. In spite of thymectomy, chemotherapy, and radiation therapy, malignant thymoma was disseminated to the thoracic cavity and no more treatment options could be utilized on admission. The patient presented with erythema that was scaly, mildly keratotic, and distributed over the face, body trunk, and extremities (Fig. 1a). The patient reported severe pruritus. Biopsy specimen of the erythema revealed superficial perivascular dermatitis with parakeratosis, hypogranulosis, dyskeratosis with satellite cell necrosis, mild acanthosis, and vacuolar change in the epidermis, and moderate infiltration of lymphocytes in the upper dermis (Fig. 1b). Direct immunofluorescence was negative (data not shown). Immunohistochemistry revealed that there were more CD8+ T cells than CD4+ T cells infiltrated in the epidermis and dermis (Fig. 1c, d). Differential diagnoses included psoriasis, lichen planus, pityriasis rosea, lichenoid drug eruption, pityriasis lichenoides chronica, and thymoma-associated GVHD-like erythroderma. psoriasis was ruled out by the presence of dyskeratosis, and parakeratosis is not usually observed in lichen planus. The clinical course was too long for pityriasis rosea, and lichenoid drug eruption could be ruled out because of the absence of eosinophils in the dermis. Furthermore, pityriasis lichenoides chronica is not usually pruritic and the eruptions are more oval than those of our case. Based on the characteristic distribution and clinical features of the erythema and pathological findings, a diagnosis of thymoma-associated GVHD-like erythroderma was made. potent topical steroid (clobetasol propionate 0.05%), systemic steroid (prednisolone 2 mg/kg/day), and cyclosporine (5 mg/kg/day) were prescribed for 2 weeks, but did not control the erythema (Fig. s1; available from http://www.medicaljournals.se/acta/content/?d oi=10.2340/00015555-1577). Intriguingly, after the initiation of oral acyclovir (15 mg/kg/day) for exacerbated oral herpes infection, the erythema began to subside. acyclovir was then switched to valacyclovir hydrochloride (15 mg/kg/day). Incidentally, we detected a high level of CMV antigenemia of up to 1,564 cells/slide, although it was only 11 cells/slide 6 months previously. The patient did not report any symptoms of retinitis, pneumonia, or colitis, thus we administered ganciclovir (5 mg/kg/day) and discontinued valacyclovir. The erythema recurred when prednisolone was tapered to 0.75 mg/kg/day; therefore, prednisolone was increased up to 1 mg/kg/day, which was not successful. Next, broadband ultraviolet Reactivation of Herpes Simplex Virus and Cytomegalovirus in a Case of Thymoma-associated Graft-versus-host Disease-like Erythroderma

Case of drug‐induced hypersensitivity syndrome with multiple skin ulcers caused by herpes simplex virus reactivation

Case of drug‐induced hypersensitivity syndrome with multiple skin ulcers caused by herpes simplex virus reactivation

Bell's Palsy/facial paralysis in an orthodontic patient: Case report

The aim of this article was to relate the occurrence of Bell's Palsy/Facial Paralysis (BP) in an orthodontic patient after you place mucosal trauma using intermaxillary elastics. The paralytic event occurred shortly after the mechanical insertion of intermaxillary elastics, with the result that the patient associates the use of the elastics with paralysis. After magnetic resonance was performed, the condition of BP was confirmed. The paralysis occurred as a result of the trauma of the mucosa with the use of elastic that reactivated herpes simplex virus.The procedure was to suspend the use of the elastics and prescription for the use of a dose of 25mg prednisolone twice a day for 10days. The patient has been followed-up for 90days, and 90% remission of the paralysis has been observed.

Increased risk of cancer after Bell’s palsy: a 5-year follow-up study

Reactivation of latent herpes simplex virus (HSV) type I or varicella-zoster virus (VZV) has been recognized as the most common pathomechanism underlying Bell's palsy. There is also increased reactivation of HSV or VZV in patients with immunosuppressed states and in cancer patients. The purpose of this study was to investigate the risk for cancer during a 5-year follow-up period after diagnosis of Bell's palsy by using a population-based dataset in Taiwan. We used data from the "Longitudinal Health Insurance Database". We identified 2,618 patients with Bell's palsy as the study cohort and randomly selected 13,090 patients to be used as a comparison cohort. Cox proportional hazards regression was performed to compare the 5-year risk of subsequent cancer between the study and comparison cohorts. We found that the incidence of cancer was 1.55 (95 % CI 1.35-1.78) per 100 person-years for patients with Bell's palsy and 1.09 (95 % CI 1.02-1.18) per 100 person-years for comparison patients. After censoring cases that died from non-cancer causes during the follow-up period and adjusting for urbanization, monthly income, geographic region, and diabetes, the hazard ratio (HR) for cancer during the 5-year follow-up period for patients with Bell's palsy was 1.43 times that for comparison patients (95 % CI 1.22-1.73). There was a particularly increased risk of oral cancer (HR = 2.49; 95 % CI 1.54-4.03) for patients with Bell's palsy compared with the other patients. We conclude that patients with Bell's palsy were at significant risk of cancer during a 5-year follow-up period after diagnosis.

Factors affecting herpes simplex virus reactivation from the explanted mouse brain

The majority of encephalitis induced by herpes simplex virus type I (HSV-1) is due to viral reactivation from latency, but few studies have investigated the factors influencing viral reactivation in the brain due to the lack of a sensitive assay. We have established an ex vivo explant assay, which induced efficient viral reactivation in the dissociated mouse brain. Applying this assay, we investigated the infection of four HSV-1 strains with varying degrees of neurovirulence in three mouse strains with different levels of susceptibility to HSV-1 infection. We found that virulent HSV-1 strains and susceptible mouse strains exhibited prolonged viral growth during acute infection, increased latent viral genomes, and efficient explant reactivation in the brain stem. Collectively, both viral neurovirulence and host susceptibility positively correlate with HSV-1 reactivation from the explanted mouse brain.

Innate-like behavior of human invariant natural killer T cells during herpes simplex virus infection

Invariant natural killer T (iNKT) cells, CD1d restricted T cells, are involved in the immune responses against various infection agents. Here we describe their behavior during reactivation of human herpes simplex virus (HSV). iNKT cells exhibit only discrete changes, which however, reached statistically significant level due to the relatively large patient group. Higher percentage of iNKT cells express NKG2D. iNKT cells down-regulate NKG2A in a subset of patients. Finally, iNKT cells enhance their capacity to produce TNF-α. Our data suggests that iNKT cells are involved in the immune response against HSV and contribute mainly to its early, innate phase.

Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era

Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era

Bell`s palsy associated with herpes simplex virus reactivation during pregnancy

BACKGROUND: Bell's palsy may result from high blood pressure, diabetes, pre-eclampsia, vascular, infectious, genetic, and immunological causes. Accord ingly, we present a case of Bell's palsy associated with her pessimplex infection during pregnancy. CASE PRESENTATION: A 33-year-old pregnant woman was admitted to our clinic with sudden on set of in ability to close the right eye, excessive tearing, asymmetrical appearance of the mouth, facial twitching, and impaired sense of taste. Medical history revealed an occurrence of herpetic rash around the upper lip one week ago. Checking of facial nerves function recognized unilateral right-sided paralysis. EMG showed se vere partial axonal peripheral truncallesion of the right facial nerve and presence of denervation. The diagno sis was based on patient's his tory, physical and neuro logical examination, as well as on laboratory tests and EMG. CONCLUSION: Our case report suggests that the peripheral facial nerve paralysis might be as sociated with the increased susceptibility to her pessimplex virus infection during pregnancy. SSM, 2012;44(1):29-31