The total dependence of amphibian metamorphosis on thyroid hormone (T₃) provides a unique vertebrate model for studying the molecular mechanism of T₃ receptor (TR) function in vivo. In vitro transcription and developmental expression studies have led to a dual function model for TR in amphibian development, i.e., TRs act as transcriptional repressors in premetamorphic tadpoles and as activators during metamorphosis. We examined molecular mechanisms of TR action in T3-induced metamorphosis by using dominant-negative receptors (dnTR) ubiquitously expressed in transgenic Xenopus laevis. We showed that T₃-induced activation of T₃ target genes and morphological changes are blocked in dnTR transgenic animals. By using chromatin immunoprecipitation, we show that dnTR bound to target promoters, which led to retention of corepressors and continued histone deacetylation in the presence of T₃. These results thus provide direct in vivo evidence for the first time for a molecular mechanism of altering gene expression by a dnTR. The correlation between dnTR-mediated gene repression and inhibition of metamorphosis also supports a key aspect of the dual function model for TR in development: during T₃-induced metamorphosis, TR functions as an activator via release of corepressors and promotion of histone acetylation and gene activation.

The exact mechanisms of HSV-1 establishment, maintenance, latency, reactivation, and also the courses of recurrent ocular infections remain a mystery. Comprehensive understanding of the HSV-1 disease process could lead to prevention of HSV-1 acute infection, reactivation, and more effective treatments of recurrent ocular disease. Animal models have been used for over sixty years to investigate our concepts and hypotheses of HSV-1 diseases. In this paper we present descriptions and examples of rabbit and mouse eye models of HSV-1 latency, reactivation, and recurrent diseases. We summarize studies in animal models of spontaneous and induced HSV-1 reactivation and recurrent disease. Numerous stimuli that induce reactivation in mice and rabbits are described, as well as factors that inhibit viral reactivation from latency. The key features, advantages, and disadvantages of the mouse and rabbit models in relation to the study of ocular HSV-1 are discussed. This paper is pertinent but not intended to be all inclusive. We will give examples of key papers that have reported novel discoveries related to the review topics.

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) controls the expression of HIV-1 viral genes and thus viral propagation and pathology. Numerous host factors participate in the regulation of the LTR promoter, including thyroid hormone (T₃) receptor (TR). In vitro, TR can bind to the promoter region containing the NF-κB and Sp1 binding sites. Using the frog oocyte as a model system for chromatin assembly mimicking that in somatic cells, we demonstrated that TR alone and TR/RXR (9-cis retinoic acid receptor) can bind to the LTR in vivo independently of T₃. Consistent with their ability to bind the LTR, both TR and TR/RXR can regulate LTR activity in vivo. In addition, our analysis of the plasmid minichromosome shows that T₃-bound TR disrupts the normal nucleosomal array structure. Chromatin immunoprecipitation assays with anti-acetylated-histone antibodies revealed that unliganded TR and TR/RXR reduce the local histone acetylation levels at the HIV-1 LTR while T₃ treatment reverses this reduction. We further demonstrated that unliganded TR recruits corepressors and at least one histone deacetylase. These results suggest that chromatin remodeling, including histone acetylation and chromatin disruption, is important for T₃ regulation of the HIV-1 LTR in vivo.

This study investigated the putative inhibitory effect of manzamine A on HSV-1 infection. Our results indicated that manzamine A effectively inhibited viral replication and infection in the cell line SIRC, a corneal cell line, at 1 µM. The existing anti-HSV-1 drug acyclovir was analyzed and showed a comparable activity at 50 µM. Plaque assays demonstrated that manzamine A reduced the release of infectious virus by 10¹¹-fold. RTPCR assays indicated that HSV-1 virion host shutoff (vhs) activity and ICP0 transcription were decreased by manzamine A treatment. These results bode well for the development of manzamines as potential leads to reduce viral infection in corneal cells and to prevent HSV-1-induced eye infections such as keratitis.