Reactivation Of Latent Virus Research Articles

Pain Management of Acute Herpes Zoster

Acute herpes zoster affects over one million Americans each year in spite of the wide spread availability of an effective preventative vaccine. Caused by reactivation of latent varicella-zoster virus in patients with weakened T-cell immunity, the disease manifests as an acute painful vesicular rash most commonly affecting the thoracic dermatomes and trigeminal nerve, although all areas of the body can be affected. In most patients, the pain and dematologic manifestations of the disease gradually resolve, but unfortunately, in 10-45% of patients, the pain and paresthesias associated with the acute phase of herpes zoster may persist beyond lesion healing. Treatment of acute herpes zoster is aimed at lessening the severity of the symptoms and shortening the course of the acute phase of the disease by use of antiviral agents combined with analgesics, topical agents, nerve blocks, steroids, and adjuvant analgesics consisting of anticonvulsants and antidepressants.

P-A3 Identification of proximal biomarkers of PKC agonist activity in HIV-1 latently infected cells

A small population of resting memory CD4+ T cells harboring transcriptionally silent, but replication competent human immunodeficiency-1 (HIV-1) proviruses is considered to be the major obstacle for HIV eradication in patients on anti-retroviral therapy (ART). Latent virus reactivation using protein kinase C (PKC) agonists is one approach the field is leveraging to flush HIV from latent reservoirs. Thus, increased understanding of the molecular mechanisms of action of this approach is necessary to inform of biological signaling as well as potential off-target effects associated with PKC agonists. We used an RNA-Seq- based approach to identify genes and pathways modulated following treatment of CD4+ T cells with PKC agonists. Primary human CD4+ T cells were treated with either PMA, Prostatin or Ingenol-3-Angelate for various time periods. At 3 and 24 hours post-treatment, cells were harvested and RNA-Seq was performed. Treatment with the three PKC agonists induced a time-dependent alteration in host cell gene expression pattern. Bioinformatic analysis revealed high similarity in the genes and pathways altered, with at least 42% of genes showing similar changes in expression between controls and the three compounds tested. Immune response pathways strongly associate with the gene expression changes observed at 3 hours post-treatment, while pathways associated with mitochondrial dysfunction and oxidative phosphorylation predominated at 24 hours. Quantitative reverse transcriptase PCR (qRT-PCR) validation of a subset of the RNA Seq data confirmed modulation of genes with higher expression levels across the 3 PKC agonists in HIV-1 latently infected Jurkat cells. Overall, our results could offer new insights into the mechanism of action of PKC agonists in latently infected cells, and therefore inform on eradication strategies for latent HIV.

Risk of Herpes Zoster and Family History: A Meta-analysis of Case-control Studies.

Background:Herpes zoster (HZ) results from the reactivation of latent varicella zoster virus (VZV) residing in dorsal root and cranial nerve ganglia. Advanced age and dysfunctional cell-mediated immune responses are well-established risk factors for VZV reactivation. There have been recent interests in whether there is an increased risk of the disease associated with a positive family history.Aims and Objectives:We aimed to conduct a meta-analysis to evaluate the association between HZ infection and family history. In addition, we investigated the dose-response relationship between HZ infection and the number of relatives with a history of HZ.Materials and Methods:Observational studies were searched from MEDLINE, EMBASE, and Cochrane Central Register from inception to April 15, 2015. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed in conducting this study. To estimate the pooled odds ratio, random-effects model of DerSimonian and Laird was used. Heterogeneity between studies was assessed using the I2 statistic. A dose-response meta-analysis with studies that reported appropriate data were done using the generalized least squares for trend method.Results:Five studies, yielding a total of 4169 subjects, were identified for meta-analysis. Cases with HZ were 3.03 (95% confidence interval [CI]: 1.86–4.94, P < 0.001) and 3.27 (95% CI: 1.75–6.10, P < 0.001) times more likely to report the first-degree relatives and total relatives with a history of HZ, respectively. A significant positive dose-response relationship between the risk of HZ infection and the number of relatives with a history of HZ was also demonstrated (P < 0.001).Conclusions:This meta-analysis demonstrated that family history is a significant risk factor for HZ infection. This risk has a dose-response relationship with the number of relatives with a history of HZ.

LGIT In Vitro Latency Model in Primary and T Cell Lines to Test HIV-1 Reactivation Compounds.

Persistent latent HIV-1 reservoirs pose a major barrier for combinatorial antiretroviral therapy (cART) to achieve eradication of the virus. A variety of mechanisms likely contribute to HIV-1 persistence, including establishment of post-integration latency in resting CD4+ T-lymphocytes, the proliferation of these latently infected cells, and the induced or spontaneous reactivation of latent virus. To elucidate the mechanisms of latency and to investigate therapeutic strategies for reactivating and purging the latent reservoir, investigators have developed in vitro models of HIV-1 latency using primary CD4+ T-lymphocytes and CD4+ T-cell lines. Several types of in vitro latency models range from replication-competent to single-round, replication-deficient viruses exhibiting different degrees of viral genomic deletion. Working under the hypothesis that HIV-1 post-integration latency is directly linked to HIV-1 promoter activity, which can be obscured by additional proteins expressed during replication, we focus here on the creation of latently infected primary human T-cells and cell lines through the single-round, replication deficient HIV-1 LGIT model. In this model the long terminal repeat (LTR) of the HIV-1 virus drives a cassette of GFP-IRES-Tat that allows testing of reactivating components and initiates a positive feedback loop through Tat expression.

How stress can overcome latency

JNK signaling alters chromatin to induce reactivation of latent herpes simplex virus.

Romidepsin in Relapsed/Refractory HTLV-1 Associated Adult T-Cell Lymphoma/Leukemia: A Case Series

Introduction: Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus -1 (HTLV-1) infection. The aggressive subtypes(acute/lymphomatous) have a median survival of 6-13 months. Presently, there is no established therapy for patients with relapsed/refractory disease. Romidepsin is bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with peripheral T-cell lymphoma who have received ≥ 1 prior systemic therapy, after demonstrating objective response rate of 25% (33 of 130), including 15% (19 of 130) complete remissions. Approaches for relapsed/refractory Peripheral T cell lymphoma(PTCL) are often applied to ATLL, although there is little data for this subtype. Neither of the two Phase II trials leading to its approval had ATLL cases. Reactivation of latent DNA viruses has been described as a consequence of immune suppression associated with this drug although its impact on HTLV-1 associated neoplasm is not known. Here we present 3 cases of relapsed refractory ATLL treated with romidepsin.Methods: We reviewed all patients with relapsed/refractory ATLL treated with romidepsin at King's County Hospital between 2012 and 2015.Results:Case 1: 43 year old male presented with multiple hyperpigmented nodules on the trunk and a 4 cm draining ulcerated left shoulder lesion. Complete blood count (CBC) was normal. Peripheral smear showed atypical lymphocytes with clover leaf pattern. CT scan Chest/abd/pelvis showed no enlarged lymphadenopathy. Punch biopsy of the skin confirmed involvement with peripheral T cell neoplasm HTLV-1 positive. Treated was initiated with EPOCH (etoposide/prednisone/vincristine/cisplatin/adriamycin) with partial response. He progressed on therapy after 4 cycles with new axillary/inguinal and retroperitoneal lymphadenopathy. Romidepsin was started at 14 mg/m2 IV Day 1, 8, 15 Q28 days. He tolerated cycle 1 well but continued to have progressive disease as evidenced by worsening hypercalcemia, atypical lymphocytosis and lymphadenopathy. Patient died 40 days after initiation of therapy from wound infection.Case 2: 37 year old male presented with diffuse lymphadenopathy and massive hepatosplenomegaly. CBC revealed white cell count (WBC) of 103.9k/mm3 with 94% lymphocytes. Bone marrow biopsy and lymph node biopsy confirmed involvement with peripheral T cell neoplasm HTLV-1 positive. He was treated with EPOCH x 2, ICE (Iphosphamide, carboplatin, etoposide) x 1 and high dose methotrexate x 1 with disease progression. He was started on Romidepsin 10 mg/m2 IV Day 1, 8, 15 Q28 days (dose reduced due to T. bili 3.5gm/dl). After first dose, patient developed severe thrombocytopenia to 20k/mm3 necessitating treatment delay and dose reduction to 6mg/m2. He had temporary response as evidenced by reduction in WBC count from 103kmm3 to 5k/mm3 and improvement in liver function. Patient received 1 cycle of therapy and died on Day 50 from disease progression.Case 3: 47 year old male presented with a 6x4 cm exophytic left forearm lesion, diffuse lymphadenopathy and normal CBC and metabolic profile. Skin biopsy confirmed CD30 positive peripheral T cell neoplasm HTLV-1 positive. Patient received 6 cycles of CHOP with complete resolution of lymphadenopathy and skin lesions. Patients stayed in remission for 12 months however relapsed with lymphocytosis to 57k/mm3, recurrence of skin lesions and diffuse lymphadenopathy. He received brentuximab x 2 cycles and ICE x 2 cycles with progressive disease. He was started on romidepsin 14mg/m2 IV Day 1, 8, 15 Q28 days. He received 1 dose and had prolonged Grade IV anemia/thrombocytopenia. He finally developed urosepsis and expired on Day 20.Conclusion: ATLL is a rare and difficult disease to manage. In our small experience of romidepsin in relapsed/refractory ATLL, patients appear to have modest response rates and higher rate of cytopenias when compared to other PTCL subtypes in clinical trials. A dedicated phase II study of romidepsin in relapsed/refractory ATLL is needed to assess its efficacy and toxicity profile in this population. Given the concerns for viral reactivation and lack of data for use of romidepsin in ATLL, it should be used cautiously. DisclosuresNo relevant conflicts of interest to declare.

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection.

Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3-heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3-homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Anti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHC-homozygous and -heterozygous Mauritian cynomolgus macaques, we have now obtained evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection.

Herpes zoster vaccination in the elderly subjects: improving awareness and uptake

Herpes zoster (HZ) is a common disease in adults and older subjects solely related to the reactivation of latent varicella zoster virus in ganglia. The incidence of the disease increases with aging and the decline of varicella zoster virus-specific cell-mediated immunity. HZ has a significant impact on the quality of life of subjects during the acute phase. Besides, pain can persist even for a long time becoming chronic. The chronic pain following HZ is called postherpetic neuralgia, and it is a debilitating long-lasting condition, characterized by metameric pain, allodynia, and hyperalgesia. Therapeutic options against HZ and postherpetic neuralgia are often suboptimal and the impact of the disease and its complications on daily living activities is significant, especially in older subjects. Nowadays, a preventive approach to the disease is possible; as a matter of fact, a high-antigen content live vaccine is available. This vaccine has a good profile in terms of immunogenicity, efficacy, effectiveness, and safety and its use may prevent both HZ and postherpetic neuralgia. Nevertheless, the evaluation of the issues raised in countries that introduced this immunization show that both provider and patient barriers could have prevented a more robust uptake of HZ vaccination. In the USA, HZ immunization storage was expensive, reimbursement was cumbersome, and supply shortages may have limited promotion by the interests of the manufacturer and provider. The doctors did not actively recommend HZ vaccination; on the other hand, subjects were mostly unaware of the HZ vaccine. Several demographic factors, including sex and educational level, could have negatively affected the coverage rates; besides, the clinicians who treat adults focus less on vaccination than those taking care of children. On the other hand, when health care profession- als undertook every effort to maximize the uptake of the shingles vaccine (eg, in the UK), the vaccine coverage rate increased very quickly.

Management and Prevention of Herpes Zoster Ocular Disease.

Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in people who have had chicken pox, usually resulting in a painful, unilateral, dermatomal, vesicular rash. Herpes zoster ophthalmicus occurs when the first division of cranial nerve V is involved. HZ is common, with approximately 1 million new cases per year in the United States, and occurs in 1 in 3 persons. Although the rate of HZ increases with age, over half of all cases occur under the age of 60 years. Complications of herpes zoster ophthalmicus include eye disease, postherpetic neuralgia (PHN), and strokes. VZV has also been found in temporal arteritis biopsies. There is growing evidence that HZ is followed by chronic active VZV infection contributing to these complications. In view of this, and the efficacy of suppressive antiviral treatment in reducing recurrent herpes simplex keratitis, a randomized controlled trial of suppressive valacyclovir to reduce new or worsening anterior segment disease and/or PHN is needed. The zoster vaccine (ZV) is safe and effective in reducing the burden of illness, severity of PHN, and incidence of HZ. It is Centers for Disease Control and Prevention recommended for persons aged 60 years and above without impaired cellular immunity, and Food and Drug Administration approved for those aged 50 and older. It is most effective in preventing HZ in recipients in their 50s. Because of underusage of the ZV, it has not impacted the epidemiology of the disease. Barriers to its use include cost, variable reimbursement, frozen storage, and lack of a strong recommendation by doctors.

Un Raro Caso di Herpes Zoster Complicato da Paralisi Asintomatica del Nervo Frenico in un Paziente in Emodialisi

Herpes Zoster (HZ) is the clinical manifestation of latent Varicella Zoster Virus (VZV) reactivation which can occur several decades after the early infection by Varicella Virus. Herpes Zoster usually affects the sensory neurons but may occasionally involve motor neurons corresponding to the dermatomes affected by skin lesions, resulting in flaccid paralysis of their muscles. Phrenic nerve paralysis is commonly caused by surgical or traumatic injuries, malignant tumors, neurodegenerative disorders or idiopathic diseases. However, in rare cases, it has been reported a diaphragmatic paralysis resulting from infection by Herpes Varicella Zoster Virus (VZV). We report a case of a 58 years old man, undergoing hemodialysis, who developed a left diaphragmatic paralysis after a typical Herpes Zoster rash involving the dermatome C3-C4 on the left side. The clinical and radiological results revealed no local causes of injury to the phrenic nerve. Hemidiaphragmatic paralysis was probably related to the infection by VZV. We asked ourselves if underdosing of the antiviral therapy (in the uremic patient) or the shortness of the treatment may have contributed to the development of this complication. However we believe that the risks resulting from overdosing outweigh the benefits. Therefore further studies, especially in ESRD, would be needed in order to evaluate if the dose adjustment and/or a prolongation of the antiviral therapy may have a protective effect on the onset of diaphragmatic paralysis.

Incidence of Herpes Zoster in relationship with Climate Factors from 2009 to 2011

Background : Herpes zoster, or shingles, is a skin or mucous infection caused by the reactivation of varicella-zoster virus (VZV). Seasonal pattern of herpes zoster incidence was reported in some countries, indicating that emergence of this disease was caused by the reactivation of latent Varicella-Zoster Virus (VZV) rather than new exposures to VZV. On the other hand, the VZV primary infection difference between tropical and temperate zones may have implications for virus reactivation as herpes zoster. The aim of this study was to identify the incidence of herpes zoster in Dr. Hasan Sadikin General Hospital Bandung, West Java related to the change of rainfall, air temperature and humidity from 2009 to 2011. Methods : A descriptive retrospective study was carried out to 341 medical records of herpes zoster patients from Dr. Hasan Sadikin General Hospital Bandung periode 2009 to 2011. Data on climate factors, i.e. rainfall, air temperature, and relative humidity, were obtained from the Indonesian Meteorology, Climatology, and Geophysical Agency. The collected data were presented using tables and figures. Result : The highest number of herpes zoster cases occured during the period when the highest annually total rainfall and annually mean relative humidity occurred. Conclusions : The finding of this study shows that herpes zoster cases have the same pattern with the rainfall and relative humidity. These findings can inform better prevention of herpes zoster. However, further research is needed to get more comprehensive understanding on this relationship. DOI : 10.15850/amj.v2n3.591

Donor CD4 T Cell Diversity Determines Virus Reactivation in Patients After HLA-Matched Allogeneic Stem Cell Transplantation

Delayed reconstitution of the T cell compartment in recipients of allogeneic stem cell grafts is associated with an increase of reactivation of latent viruses. Thereby, the transplanted T cell repertoire appears to be one of the factors that affect T cell reconstitution. Therefore, we studied the T cell receptor beta (TCRβ) gene rearrangements of flow cytometry–sorted CD4+ and CD8+ T cells from the peripheral blood of 23 allogeneic donors before G-CSF administration and on the day of apheresis. For this purpose, TCRβ rearrangements were amplified by multiplex PCR followed by high-throughput amplicon sequencing. Overall, CD4+ T cells displayed a significantly higher TCRβ diversity compared to CD8+ T cells irrespective of G-CSF administration. In line, no significant impact of G-CSF treatment on the TCR Vβ repertoire usage was found. However, correlation of the donor T cell repertoire with clinical outcomes of the recipient revealed that a higher CD4+ TCRβ diversity after G-CSF treatment is associated with lower reactivation of cytomegalovirus and Epstein–Barr virus. By contrast, no protecting correlation was observed for CD8+ T cells. In essence, our deep TCRβ analysis identifies the importance of the CD4+ T cell compartment for the control of latent viruses after allogeneic stem cell transplantation.

Varicella-zoster virus-specific cell-mediated immunity in Ramsay Hunt syndrome.

The etiology of Ramsay Hunt syndrome (Hunt syndrome) is reactivation of latent varicella-zoster virus (VZV) in the geniculate ganglion of the facial nerve, leading to neuritis. Although the mechanism of the VZV reactivation is unclear, one possibility is that the reactivation involves a low level of VZV-specific cell-mediated immunity (CMI). The aim of this study was to clarify the characteristics of the VZV-specific CMI in Hunt syndrome compared to that in Bell's palsy, and to obtain clues to its role in the development of Hunt syndrome. Prospective study. We determined the median spot numbers and examined VZV-specific CMI in patients with Hunt syndrome and with Bell's palsy using interferon-γ enzyme-linked immunospot (ELISPOT) assays. We analyzed the relationship between the value of VZV-specific CMI and days from disease onset. The median spot number in Hunt syndrome (87.3 spot-forming cells [SFCs]/4 × 10(5) peripheral blood mononuclear cells [PBMCs]) was higher than that in Bell's palsy (62.3 SFCs/4 × 10(5) PBMCs). Hunt syndrome showed a strong relationship between the ELISPOT count and days from onset (r = 0.65). Within the first 5 days from onset, no ELISPOT counts higher than 80 SFCs/4 × 10(5) PBMCs were observed. On the other hand, no correlation was observed between the ELISPOT count and days from onset in patients with Bell's palsy (r = -0.19). These results suggest that VZV-specific CMI in Hunt syndrome is low at disease onset and increases rapidly thereafter. Consequently, reduced VZV-specific CMI may play an important role in the reactivation of VZV in the facial nerve, leading to Hunt syndrome.

Herpes Zoster and Postherpetic Neuralgia: Practical Consideration for Prevention and Treatment.

Herpes zoster (HZ) is a transient disease caused by the reactivation of latent varicella zoster virus (VZV) in spinal or cranial sensory ganglia. It is characterized by a painful rash in the affected dermatome. Postherpetic neuralgia (PHN) is the most troublesome side effect associated with HZ. However, PHN is often resistant to current analgesic treatments such as antidepressants, anticonvulsants, opioids, and topical agents including lidocaine patches and capsaicin cream and can persist for several years. The risk factors for reactivation of HZ include advanced age and compromised cell-mediated immunity (CMI). Early diagnosis and treatment with antiviral agents plus intervention treatments is believed to shorten the duration and severity of acute HZ and reduce the risk of PHN. Prophylactic vaccination against VZV can be the best option to prevent or reduce the incidence of HZ and PHN. This review focuses on the pathophysiology, clinical features, and management of HZ and PHN, as well as the efficacy of the HZ vaccine.

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.

Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination

ObjectiveTo determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. Patients and MethodsPatients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. ResultsA total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). ConclusionWe found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines.

Herpes zoster-associated mortality in Europe: a systematic review.

BackgroundReactivation of latent varicella zoster virus, partly due to age-related immunosenescence and immunosuppressive conditions, results in herpes zoster (HZ) and its associated complications. The management of the most important complication, post-herpetic neuralgia (PHN), is challenging, particularly in the elderly, and is generally unsatisfactory. No previous reviews have reported the incidence of HZ-associated mortality.MethodsWe carried out a systematic literature review to identify studies and databases providing data for HZ-associated mortality in adults aged ≥50 years in Europe.ResultsWe identified 12 studies: Belgium (1); France (1); Germany (1); the Netherlands (2); Portugal (1); Spain (4) and England/Wales (2) and 4 databases from Europe: France; Germany and England/Wales. The incidence was available from eight studies; it was highest in those aged ≥95 in France (19.48/100,000). In the European (WHO) database, the overall mortality ranged from 0 to >0.07/100,000. The age- and gender-specific HZ mortality rates from the other databases showed that while in younger age groups the HZ mortality rate was higher in males, in older patients the rate was much higher in women. The case fatality rate was 2 and 61/100 000 in those 45–65 and ≥65 years, respectively. A similar increase with age was seen for the hospital fatality rate; 0.6% in those 45–65 years in the UK and 7.1% in those ≥80 in Spain.ConclusionsAlthough the data were sparse and heterogeneous, HZ-associated mortality clearly increases with age. In addition, the elderly who develop HZ often have underlying diseases and are at increased risk of functional decline and loss of independence. Mortality should be taken into account in health-economics models.

Bacterial Short Chain Fatty Acids Push All The Buttons Needed To Reactivate Latent Viruses.

The genomes of herpesviruses and HIV become silent during latency through multiple chromatin silencing mechanisms including: histone deacetylation, repressive histone methylation, and DNA methylation. Reactivation of the latent virus requires removal of the chromatin silencing marks and their replacement by activating modifications such as histone acetylation and activating histone methylation. In a complementary mechanism, RNA Polymerase II (RNAP II) elongation is regulated by the positive transcription elongation factor b (P-TEFb)-dependent phosphorylation of Ser2 residues on its C-terminal domain. In resting T-cells latently infected by HIV, expression of P-TEFb is restricted. We found that a group of short chain fatty acids (SCFAs) produced by oral bacteria not only promote histone acetylation but also change the histone methylation dynamics by decreasing repressive histone methylation while increasing activating histone methylation. SCFAs also block DNA methylation and activate P-TEFb to enable elongation of stalled RNA polymerase II. Thus these molecules do not simply act as histone deacetylase (HDAC) inhibitors as previously claimed. Instead, they impact multiple complementary epigenetic regulatory mechanisms to promote highly efficient reactivation of latent viruses.

Cell-mediated immune responses to ZOSTAVAX© are characterized by a boost in polyfunctional central memory T cells (VAC4P.1115)

Abstract Herpes Zoster (HZ) is a debilitating disease caused by reactivation of latent varicella-zoster virus (VZV). ZOSTAVAX is approved for the prevention of HZ and its complications in individuals 50 years and older in many countries around the world. The mechanistic immune correlates of protection and VZV antigens responsible for induction of protective CMI are not defined. To screen for dominant VZV antigens, whole blood from subjects pre-and-post ZOSTAVAX vaccination were assessed for production of IFN-ϒ, IL-2 and, TNF-α. VZV antigens eliciting high cytokine levels were used to stimulate PBMC and intracellular cytokine staining performed. We show that the VZV antigens that led to a boost in the frequency of polyfunctional CD4+ T cells (TCD4+) were IE63&amp;gt;IE62&amp;gt;gB&amp;gt;ORF9&amp;gt;gE. Polyfunctional TCD4+ produced higher levels of cytokines than monofunctional cells, and a boost in expression of cytokines was observed, post-ZOSTAVAX. Phenotypic characterization of polyfunctional TCD4+ demonstrated that they are TCM cells. Notably, we detected ORF9-specific CD8+ T cells in 52% of subjects tested, however whether these responses are cross-functional or VZV-specific needs to be determined. Overall, these studies outline the CMI that may correlate with ZOSTAVAX protection.

A rare case of Ramsay Hunt syndrome following temporomandibular joint surgery

Surgical approaches to the temporomandibular joint (TMJ) have been designed specifically to minimize injury to the temporal branch of the facial nerve. In spite of this, facial nerve dysfunction occurs in 1–32% of patients undergoing TMJ surgery. Ramsay Hunt syndrome is characterized by peripheral facial paralysis that often involves other cranial nerves, mostly cranial nerve VIII. The pathology is attributed to the reactivation of latent varicella zoster virus in the geniculate ganglion. The diagnosis is based mostly on history and physical findings. Surgical procedures have been known to reactivate varicella zoster virus, but Ramsay Hunt syndrome subsequent to TMJ surgery has not been described yet. This report describes a case of Ramsay Hunt syndrome associated with TMJ surgery. Because of the relatively high incidence of facial nerve dysfunction associated with TMJ surgery, patients with varicella zoster virus reactivation may initially be misdiagnosed with iatrogenic facial palsy, or vice versa.