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.
Keywords: 2-Morpholin-4-yl-8-phenylchromen-4-one; 4,5,6,7-Tetrabromo-2H-benzotriazole; Casein kinase 2; Differentiation; Herpes simplex virus; Phosphoinositide 3-kinase; Tetrabrominated cinnamic acid; Thyroid hormone.