A Cohort Historical Analysis of the Relationship between Thyroid Hormone Malady and Alpha-Human Herpesvirus Activation
A number of physiological factors have been suggested to participate in the alpha- Human Herpesvirus (αHHV) reactivation, such as hormonal aberration. Thyroid hormone (TH) was shown to play a suppressive role in Herpes Simplex Virus Type-1 (HSV-1) gene expression and replication in cell culture and animal models. We hypothesize that reactivation of αHHV in humans may be due to, at least in part, by TH status.
Prior to implementing a full-scale population-based prospective inquiry into this hypothesis, a pilot study using a medical claims data base and a case-controlled, retrospective cohort investigation was conducted to develop a hypothetical link between TH complication and αHHV reactivation. Using diagnostic codes for treating thyroid disorders and αHHV infections as proxies for biologic/clinic outcomes, we queried a large, comprehensive hospital data base to construct two patient cohorts: Cohort 1 was comprised of patients receiving TH diagnoses over a twelve-year period, and Cohort 2 was composed of patients not receiving TH diagnoses during this period. Diagnoses of αHHV were recorded for each cohort and the difference in the frequency was examined for statistical significance. Demographic analyses such as age, gender, etc were also performed.
Using 2×2 contingency table analyses and Statistical Analysis Software (SAS), an Odds Ratio (OR) of 2.83 was observed for the total population of 21 years old and above with a chi-square of 61.55 and p < 0.001, confirming that a severe significant difference was found between these two cohorts. This result suggested that patients with αHHV diagnosis have higher chances to have TH disorders. Additional investigation revealed that female were at higher/significant probability to have both TH and αHHV diagnosis, indicating a link of αHHV reactivation to a complex hormonal profile difference between genders. Our observation indicated that female patients of 21 years of age and above exhibited a very high incidence (OR of 3.40, p < 0.001) compared to the male groups (OR of 1.91, p < 0.05), indicating the possibility that hormonal alteration in females maybe transient but robust and can lead to αHHV reactivation more often than the males.
These results indicated that TH dysfunction may have implication in αHHV pathogenesis and females exhibited much higher probability to suffer αHHV reactivation due to TH disruption. Although the results from this pilot study have limitations and require additional controlled clinical examination such as more detailed patient records, lab data, therapeutic outcome, etc, it provides a tool to assess the effects of hormone imbalance on virus reactivation by retrospective analyses using existing large scale data base.
Influence of Thyroid Hormone Disruption on the Incidence of Shingles
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.
New insights on thyroid hormone mediated regulation of herpesvirus infections
Thyroid hormone (T3) has been suggested to participate in the regulation of herpesvirus replication during reactivation. Clinical observations and in vivo experiments suggest that T3 are involved in the suppression of herpes virus replication. In vitro, differentiated LNCaP cells, a human neuron-like cells, further resisted HSV-1 replication upon addition of T3. Previous studies indicate that T3 controlled the expression of several key viral genes via its nuclear receptors in differentiated LNCaP cells. Additional observation showed that differentiated LNCaP cells have active PI3K signaling and inhibitor LY294002 can reverse T3-mediated repression of viral replication. Active PI3K signaling has been linked to HSV-1 latency in neurons. The hypothesis is that, in addition to repressing viral gene transcription at the nuclear level, T3 may influence PI3K signaling to control HSV-1 replication in human neuron-like cells. We review the genomic and non-genomic regulatory roles of T3 by examining the phosphoinositide 3-kinase (PI3K) pathway gene expression profile changes in differentiated LNCaP cells under the influence of hormone.
The results indicated that 15 genes were down-regulated and 22 genes were up-regulated in T3-treated differentiated LNCaP cells in comparison to undifferentiated state. Of all these genes, casein kinase 2 (CK2), a key component to enhance PI3K signaling pathway, was significantly increased upon T3 treatment only while the cells were differentiated. Further studies revealed that CK2 inhibitors tetrabrominated cinnamic acid (TBCA) and 4, 5, 6, 7-tetrabromo-2H-benzotriazole (TBB) both reversed the T3-mediated repression of viral replication. Together these observations suggested a new approach to understanding the roles of T3 in the complicated regulation of HSV-1 replication during latency and reactivation.