A global HSV-1 gene repression occurs during latency in sensory neurons where most viral gene transcriptions are suppressed. The molecular mechanisms of gene silencing and how stress factors trigger the reactivation are not well understood. Thyroid hormones are known to be altered due to stress, and with its nuclear receptor impart transcriptional repression or activation depending upon the hormone level. Therefore we hypothesized that triiodothyronine (T3) treatment of infected differentiated neuron like cells would reduce the ability of HSV-1 to produce viral progeny compared to untreated infected cells. Previously we identified putative thyroid hormone receptor elements (TREs) within the promoter regions of HSV-1 thymidine kinase (TK) and other key genes. Searching for a human cell line that can model neuronal HSV-1 infection, we performed HSV-1 infection experiments on differentiated human neuroendocrine cells, LNCaP. Upon androgen deprivation these cells undergo complete differentiation and exhibit neuronal-like morphology and physiology. These cells were readily infected by our HSV-1 recombinant virus, expressing GFP and maintaining many processes iconic of dendritic morphology. Our results demonstrated that differentiated LNCaP cells produced suppressive effects on HSV-1 gene expression and replication compared to its undifferentiated counterpart and T3 treatment have further decreased the viral plaque counts compared to untreated cells. Upon washout of the T3 viral plaque counts were restored, indicating an increase of viral replication. The qRT-PCR experiments using primers for TK showed reduced expression under T3 treatment. ChIP assays using a panel of antibodies for H3 lysine 9 epigenetic marks showed increased repressive marks on the promoter regions of TK. In conclusion we have demonstrated a T3 mediated quiescent infection in differentiated LNCaP cells that has potential to mimic latent infection. In this HSV-1 infection model thyroid hormone treatment caused decreased viral replication, repressed TK expression and increased repressive histone tail marks on the TK promoter.
SUMMARY The reactivation of dormant alpha-Human Herpes Virus (αHHV) has been attributed to various causes often referred to as stressors. However, no clinical study investigating the relationship between stressors and reactivation exists in humans at this time. Herpes Simplex Virus Type-1 (HSV-1), an important αHHV, was shown to have its gene expression and replication regulated by Thyroid hormone (TH) using molecular biology approaches. Varicella Zoster Virus (VZV) is categorized in αHHV superfamily and shares similar homology with HSV-1. We hypothesize that a history of TH imbalance may be associated with the incidence of shingles (VZV reactivation). This current pilot study, based on a hospital medical claim database, was conducted as a retrospective case-controlled investigation to determine if a putative link between TH imbalance and incidence of shingles is present. An OR of 2.95 with a Chi-square of 51.74 was calculated for the total population diagnosed with TH disruption and shingles. Further analyses indicated that African American males exhibited much higher chance of simultaneous diagnoses. These results showed that a TH imbalance history may affect VZV reactivation at different incidence rates in different races and age groups.
Previously we showed that thyroid hormone (T3) regulated the Herpes Simplex Virus Type -1 (HSV-1) gene expression and replication through its nuclear receptor TR via histone modification and chromatin remodeling in a neuroblastoma cell line neuro-2a cells (N2a). This observation suggested that T3 regulation may be neuron-specific and have implication in HSV-1 latency and reactivation. In this study, our in vitro latency/reactivation model demonstrated that removal of T3 can de-repress the HSV-1 replication and favor reactivation. Transfection studies and infection assays indicated that HSV-1 thymidine kinase (TK), a key viral gene during reactivation, was repressed by TR/T3 in cells with neuronal origin but not in non-neuronal cells. Additional studies showed that RCC1 (Regulator of Chromosome Condensation 1) was sequestered but efficiently detected upon viral infection in N2a cells. Western blot analyses indicated that addition of T3 repressed the RCC1 expression upon infection. It is likely that diminution of RCC1 upon infection in neuronal cells under the influence of TR/T3 may lead to repression of viral replication/gene expression thus promote latency. Together these results demonstrated that TR/T3 mediated regulation is specific to neuronal cells and differential chromosome condensation may play a critical role in this process.
Objectives: The first aim of this study is to collect individual-level patient data for a retrospective cohort study examining the demographics of patients diagnosed with Alpha Human Herpes Viruses (α -HHV) infection, and patients with low Thyroid levels (Thyroid disorder) over a 6-year period. The second aim is to test statistically that low Thyroid levels are related to higher prevalence of α -HHV. MethOds: The data will be obtained from Peninsula Regional Medical Center located in Salisbury, Maryland. The adjusted medical claims will be identified using ICD-9-CM codes for the study period 2006-2012 of Thyroid disorders (240XX-246XX), HSV-1 (054XX) and VZV (053XX). The unique patients included in the sample will be identified with at least one medical claim for Thyroid disorder, and α -HHV diagnosis during the study period. Statistical analyses will be done using 2x2 contingency table developed by using patients with Thyroid disorder only, patients with α -HHV diagnosis only, patients that have both Thyroid disorder plus α -HHV diagnoses, and all patients without Thyroid or α -HHV diagnosis. The abstraction of the data will be done using Microsoft ® Access and the statistical analysis will be done using SAS ® 9.3. Results:The preliminary analysis of the data revealed there were 4,551 patients with Thyroid disorder only, 217 patients with α -HHV diagnosis only, 85 patients that have both Thyroid disorder plus α -HHV diagnoses, and 1,46,963 patients without Thyroid or α -HHV diagnosis. The Odds ratio = 12.65 and p-value < 0.0001 (95% confidence Interval). cOnclusiOns: The preliminary analysis reveals that odds of α -HHV reactivations are approximately twelve times higher for the individuals with Thyroid disorders. And, Thyroid disorders are significantly associated with higher prevalence of α -HHV. PDB11 comPositE quality mEasurE (cqm) attainmEnt in ovErwEight/oBEsEPatiEnts with tyPE 2 DiaBEtEs mEllitus trEatED with canagliflozin 300 mg (cana) or sitagliPtin 100 mg (sita)
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