Herpes Simplex Virus Reactivation Research Articles

Frequency of Oral Mucositis and Local Virus Reactivation in Herpes Simplex Virus Seropositive Children with Myelosuppressive Therapy.

Oral mucositis (OM) is a common chemo- and radiotherapy adverse effect in oncological pediatric patients. Herpes simplex virus (HSV) infection can cause a severe clinical course. We hypothesize, that HSV seropositivity is a risk factor for local HSV-1 reactivation and increased frequency of OM in patients with myelosuppressive therapies. We evaluated the prevalence of seropositivity of HSV-1 between June 2011 and April 2014 in patients with potential oncological disease and correlated it to the frequency of OM and local viral reactivation in OM under myelosuppressive therapy. The overall rate of HSV-seropositivity in our cohort was 22%. 48 patients underwent myelosuppressive therapy. Of these, 7 were HSV-1 IgG positive and 41 negative. All patients with OM under myelosuppressive therapy and positive local swab for viral HSV (l-PCR) were HSV-1 IgG positive before the start of therapy (100%). The absolute risk for OM in HSV-1 IgG positive patients was increased by 58.5% (95%CI: 20.0 - 72.2%) corresponding to a relative risk (RR) of 2.4 (95%CI: 1.7-3.5, P=0.009). The multivariable adjusted OR to suffer 2 or more OM episodes in HSV-1 IgG positivity was 8.8 (95%CI: 1.5-95.8, P=0.014). In HSV-1 IgG positive patients half of the OM episode showed HSV reactivation, and the risk for multiple OM episodes was increased. These patients should be investigated for HSV-infection in every OM episode. Prophylactic and preemptive therapeutic measures should be discussed early, but prospective data on HSV prophylaxis and preemptive treatment is required.

Herpes Simplex Virus Reactivation as a Complication of Photodynamic Therapy: A Case Report

Herpes Simplex Virus Reactivation as a Complication of Photodynamic Therapy: A Case Report

Therapeutic immunization with a mixture of herpes simplex virus 1 glycoprotein D-derived “asymptomatic” human CD8+ T-cell epitopes decreases spontaneous ocular shedding in latently infected HLA transgenic rabbits: association with low frequency of local PD-1+ TIM-3+ CD8+ exhausted T cells.

Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the efficacy of a therapeutic vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8(+) T cells from "naturally" protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8(+) T-cell epitopes (gD(53-61), gD(70-78), and gD(278-286)) were linked with a promiscuous CD4(+) T-cell epitope (gD(287-317)) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Nε-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8(+) T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8(+) T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1(+) TIM-3+ CD8(+) T cells. The results underscore the potential of an ASYMP CD8(+) T-cell epitope-based therapeutic vaccine strategy against recurrent ocular herpes. Seventy percent to 90% of adults harbor herpes simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide vaccine that contains exclusively human “asymptomatic” CD8(+) T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic herpes vaccine.

Large Amounts of Reactivated Virus in Tears Precedes Recurrent Herpes Stromal Keratitis in Stressed Rabbits Latently Infected with Herpes Simplex Virus

Aim: Recurrent herpetic stromal keratitis (rHSK), due to an immune response to reactivation of herpes simplex virus (HSV-1), can cause corneal blindness. The development of therapeutic interventions such as drugs and vaccines to decrease rHSK have been hampered by the lack of a small and reliable animal model in which rHSK occurs at a high frequency during HSV-1 latency. The aim of this study is to develop a rabbit model of rHSK in which stress from elevated temperatures increases the frequency of HSV-1 reactivations and rHSK.Materials and methods: Rabbits latently infected with HSV-1 were subjected to elevated temperatures and the frequency of viral reactivations and rHSK were determined.Results: In an experiment in which rabbits latently infected with HSV-1 were subjected to ill-defined stress as a result of failure of the vivarium air conditioning system, reactivation of HSV-1 occurred at over twice the normal frequency. In addition, 60% of eyes developed severe rHSK compared to <1% of eyes normally. All episodes of rHSK were preceded four to five days prior by an unusually large amount of reactivated virus in the tears of that eye and whenever this unusually large amount of reactivated virus was detected in tears, rHSK always appeared 4–5 days later. In subsequent experiments using well defined heat stress the reactivation frequency was similarly increased, but no eyes developed rHSK.Conclusions: The results reported here support the hypothesis that rHSK is associated not simply with elevated reactivation frequency, but rather with rare episodes of very high levels of reactivated virus in tears 4–5 days earlier.

Occurrence of Herpes Simplex Virus Reactivation Suggests a Mechanism of Trigeminal Neuralgia Surgical Efficacy

Common to the types of surgery that are effective for the treatment of trigeminal neuralgia (TN) is reactivation of herpes simplex virus (HSV). It is likely that such HSV reactivation following surgery indicates altered trigeminal ganglion neuron function, which was caused by the surgery. It is not thought that HSV infection is related to the cause of TN or that HSV reactivation is important for surgical treatment efficacy. Rather, it is thought that HSV reactivation is a marker of altered trigeminal ganglion neuron function resulting from the TN surgery. It is suggested that HSV reactivation is a surrogate marker of ganglion neuron injury. The correlation between effective types of surgery and evidence that they alter ganglion neuron function suggests that altered trigeminal ganglion neuron function may be the basis of the surgical efficacy.

Risk Factors and Clinical Outcome for Herpes Simplex Virus Reactivation in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Risk Factors and Clinical Outcome for Herpes Simplex Virus Reactivation in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Kaposi′s varicelliform eruption: A case series

Kaposi's varicelliform eruption is a rare and potentially fatal viral infection caused mainly by reactivation of herpes simplex virus. It concomitantly occurs with pre-existing skin conditions, mostly atopic dermatitis, so it is predominately found in children. We present a case series that includes four adults, familial cases, and previously healthy patients. We also highlight clinical features, associations and therapeutic options.

Reactivation of herpes simplex virus-1 following epilepsy surgery.

PurposeThe present study reports a case of encephalitis due to herpes simplex virus-1 (HSV-1), following surgical manipulation of the site of a primary infection.MethodsHerpes simplex virus-1 infection was confirmed by CSF PCR and DNA sequencing.ResultsThe patient was an 11-year-old girl who required temporal lobe surgery for epilepsy. She had meningoencephalitis due to HSV at the age of 20 months, and she was treated with acyclovir. Three years later, the patient developed uncontrolled seizures that became more frequent and changed in character at 11 years of age. On the 12th postoperative day, she developed fever and seizures, and she was diagnosed with HSV-1 by positive CSF PCR. She was treated with acyclovir (30 mg/kg/day for 21 days). In this report, we describe the patient and review the relevant literature.ConclusionThe authors stress the potential risk of reactivation of HSV encephalitis after intracranial surgery. Herpes simplex virus encephalitis must be considered in neurosurgical patients who develop postoperative seizures and fever.

Identification of novel virus-specific antigens by CD4+ and CD8+ T cells from asymptomatic HSV-2 seropositive and seronegative donors

Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2pos) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS™, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2pos) and virus-exposed seronegative (HSV-2neg) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2neg or asymptomatic HSV-2pos individuals, compared to symptomatic recurrent HSV-2pos subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.

Herpes simplex virus reactivation as a trigger of mucous lesions in pemphigus vulgaris

Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not been established. To establish the association with PV and herpes simplex virus (HSV). We examined saliva for the presence of HSV DNA after the onset of PV initially localized to the oral lesions in addition to conventional serological tests and immunohistochemistry. We successfully detected high levels of HSV DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex. The prevalence (37·5%) of detecting HSV DNA in the patients with PV was lower than that of eczema herpeticum (56·5%), but comparable to that in patients with herpes labialis (30·0%). Copy numbers of the HSV DNA were rather higher than those with herpes labialis and with eczema herpeticum. In general, detection of HSV DNA in saliva was transient and restricted to the earliest phase of the disease. In addition, anti-HSV immunoglobulin (Ig) G titres in patients with PV were significantly higher than those in patients with virologically confirmed HSV-induced disorders. All salivary HSV DNA-positive patients with PV had run a more complex, intractable course refractory to conventional therapy. Detection of HSV DNA in saliva is a useful and noninvasive, quantitative method for establishing the role of HSV in the pathogenesis of PV and for identifying individuals at greater risk for subsequently developing refractory PV.

In vivo reactivation of latent herpes simplex virus 1 in mice can occur in the brain before occurring in the trigeminal ganglion.

Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ. Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain.

HSV oropharyngeal shedding among HIV-infected children in Tanzania.

Herpes simplex virus (HSV) oral shedding has not been studied among HIV-positive children in Africa. We sought to evaluate longitudinal oral HSV reactivation in HIV-positive and -negative children. Twenty HIV-positive antiretroviral-naive and 10 HIV-negative children aged 3-12 years in Tanzania were followed prospectively for 14 days. Oral swabs were collected daily and submitted for HSV DNA PCR analysis. Clinical data were collected via chart review and daily diaries. HSV DNA was detected in 10 (50%) of HIV-positive and 4 (40%) of HIV-negative children. Children who shed HSV had virus detected in a median of 21.4% of samples; shedding was intermittent. Median CD4 count among HIV-infected children was 667 cells/µL in those with positive HSV DNA and 886 cells/µL in those who were negative (p = 0.6). Of the HIV-positive children reporting prior sores, five (83%) had positive HSV swabs, whereas the one HIV-negative child with prior sores did not have a PCR-positive swab. HSV is detected frequently in children with and without HIV. HIV-infected children reporting oral sores have a high rate of HSV detection. Given the proven strong interactions between HIV and HSV, further study of co-infection with these viruses is warranted in children.

Possible Neonatal Herpes Simplex Virus (HSV) Acquired Postpartum from Maternal Oral HSV Reactivation after Neuraxial Morphine.

In this report, we describe a case of a neonatal oral herpes simplex virus (HSV) infection possibly acquired from a mother who had oral HSV reactivation in association with neuraxial morphine. Neuraxial morphine is commonly administered for postpartum analgesia after cesarean delivery. While there is evidence that neuraxial morphine increases the risks of oral HSV reactivation in parturients, there has been no report of neonatal HSV infection directly acquired from a mother who had HSV recurrence from neuraxial morphine.

A case series using famciclovir in stem cell transplant recipients with valacyclovir hypersensitivity reactions

Herpes simplex virus and varicella zoster virus reactivation can occur in up to 32% and 40% of patients, respectively in the first year post-transplant without prophylaxis. Antiviral therapy consisting of acyclovir or valacyclovir is recommended for at least 1 year post stem cell transplant per evidence-based guidelines. In the event of a contraindication or hypersensitivity reaction to either drug, an alternative is essential based on the proven efficacy in reducing clinically significant herpes simplex virus and varicella zoster virus reactivations. We report two cases of successful initiation of famciclovir in stem cell transplant recipients experiencing hypersensitivity to valacyclovir or acyclovir. In both cases, there were no hypersensitivity reactions or breakthrough viral infections after famciclovir initiation but this observation is limited by a small patient population. Due to the limited data available, famciclovir appears to be a reasonable option in immunocompromised patients with a mild valacyclovir or acyclovir hypersensitivity reaction.

What role do viruses play in nosocomial pneumonia?

Viruses are an increasingly recognized cause of community-acquired pneumonia (CAP), but their exact role in nosocomial pneumonia is still debated. This review focuses on the role of viruses as a cause of nosocomial pneumonia. Respiratory viruses may be responsible for healthcare-associated pneumonia, because affected patients and those with CAP have the same risk factors for viral disease. In mechanically ventilated patients, viruses belonging to the Herpesviridae family, namely herpes simplex virus (HSV) and cytomegalovirus, can be reactivated and cause bronchopneumonitis or ventilator-associated pneumonia, respectively. Recent results confirmed the high rate of HSV reactivation in the distal airways of mechanically ventilated patients, and that patients with high virus loads (>10(5) copies/ml of bronchoalveolar lavage fluid) have poorer outcomes than those with low or no virus load. However, the responsibility of mimivirus, initially described as a possible cause of pneumonia, was not confirmed for nosocomial pneumonia. Respiratory viruses are mainly responsible for CAP, but they may also cause healthcare-associated pneumonia. HSV bronchopneumonitis and cytomegalovirus pneumonia are not rare diseases, and patients with Herpesviridae lung infections have worse prognoses than those without. Whether or not those Herpesviridae infections are responsible for true morbidity or morbidity remains to be determined.

Early collection of saliva specimens from Bell's palsy patients: Quantitative analysis of HHV-6, HSV-1, and VZV

Bell's palsy is the most common cause of facial paralysis. Although it has been associated with diabetes mellitus, hypertension, pregnancy, and preeclampsia, the etiology of Bell's palsy remains unknown. The reactivation of latent herpes simplex virus (HSV) or varicella-zoster virus (VZV) with subsequent inflammation and entrapment of the facial nerve in the narrow labyrinthine segment has been implicated as a cause of facial paralysis, but the active role of these viruses in Bell's palsy is still discussed. This study quantified HSV-1 DNA, VZV DNA, and HHV-6 DNA in 95 saliva samples collected from patients within 48 hr from the onset of paralysis. HSV-1, VZV, and HHV-6 were detected in 13%, 3%, and 61% of patients, respectively. The detection rate did not differ significantly between patients and a control group of healthy donors. Interestingly, however, the value of HHV-6 DNA copies was significantly higher than that detected in healthy donors. In addition, the mean value of HHV-6 DNA recorded in patients who had at least a one grade improvement of palsy at the first visit was significantly lower than that detected in patients who showed no change in facial palsy grade or an increase of at least one grade. These findings call into question the role of HSV-1 and VZV in the etiology of Bell's palsy, and suggest that HHV-6 may be involved in the development of the disease or that the underlying disease mechanism might predispose patients to HHV-6 reactivation.

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4(+) and CD8(+) T cells were quantified by immunofluorescence, and HSV-specific CD4(+) T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8(+) T cells compared to control tissue (27 versus 13 cells/mm(2), P = 0.03) and identified HSV-specific CD4(+) T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract. This detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8(+) T cells compared to control tissue, and HSV-specific CD4(+) T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract.

Cord blood graft composition impacts the clinical outcome of allogeneic stem cell transplantation

Despite routine use of umbilical cord blood (CB) grafts as stem cell source for allogeneic stem cell transplantations, much remains unknown regarding their cell composition and correlation with clinical outcome. We analyzed material from 30 CB units used for allogeneic hematopoietic stem cell transplantation by multicolor flow cytometry. Phenotypic data were correlated with various clinical outcomes such as survival, graft-versus-host disease (GVHD), relapse, rejection, viral reactivation, and bacteremia. We found that above-median frequencies of CD69+ T cells, naïve CD8+ T cells, and CD127+ B cells in the CB graft were each associated with significantly improved patient survival. Moreover, a statistically significant correlation was seen between higher levels of CD94+ T cells and herpes simplex virus and varicella zoster virus reactivation post transplantation. A similar correlation was seen for the frequency of CD95+ cells in total CD3+, as well as CD4+ and CD8+ T-cell subsets, and viral reactivation. Finally, a higher frequency of naïve CD8+ T cells was associated with the incidence of acute GVHD. Our study highlights the importance of further exploration of graft composition before CB transplantation as a tool for risk prediction.

Evaluation of Herpes Simplex Virus Infection Morbidity and Mortality in Pancreas and Kidney-Pancreas Transplant Recipients

BackgroundInfections remain a major cause of morbidity and mortality in solid organ transplant recipients. An increased risk of up to 50% of herpes simplex virus (HSV) reactivation in transplant recipients in the first months posttransplantation was well-documented during the pre-cytomegalovirus prophylaxis era. Previous reports suggest that these patients are likely to experience a more aggressive disease course and a higher rate of acyclovir-resistant HSV. No data currently exist regarding the course of HSV infection in pancreas or pancreas-kidney transplant (PKT) recipients. The goal of this study was to evaluate the incidence and severity of HSV infections in pancreas transplant and PKT recipients. Study DesignWe analyzed a transplant patient database of the Royal Victoria Hospital to identify 137 pancreas transplant or PKT performed between January 1999 and October 2010. A retrospective chart review was subsequently performed to evaluate the incidence and severity of herpetic infections post transplantation. ResultsOur findings show that the incidence of HSV infection in our patients was approximately 10% (10/98 cases). The majority of infections (80%) took place within the first 2 years after the transplantation. Most patients (90%) experienced a uniform, mild disease course and responded well to treatment. One patient died of an unrelated cause. Six patients were treated in hospital with a mean stay of 12.3 ± 6.35 days. The initial immunosuppressive regimen remained unchanged for half of the affected patients. None of our patients developed a drug-resistant HSV. ConclusionThese findings are intriguing and warrant a larger, multicenter, prospective study. Most important, they suggest that the new incidence of HSV reactivation is now much lower in the “cytomegalovirus prophylaxis era” and that with timely diagnosis and proper treatment most patients recover well from their HSV infections and respond to the current treatment regimens.

Herpes Simplex Virus Reactivation and Disease during Treatment for Childhood Acute Lymphoblastic Leukemia

Herpes Simplex Virus Reactivation and Disease during Treatment for Childhood Acute Lymphoblastic Leukemia