DeLuca Lab

Neal A. DeLuca, PhD
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547 Bridgeside Point II
450 Technology Dr.
Pittsburgh, PA 15219

Repression and activation of persisting HSV genomes: Herpes simplex virus can undergo either a productive infection, where all the viral genes are expressed culminating in the production of progeny virus and cell death, or it can enter a latent state, which is characterized by the relative lack of viral gene expression, genome persistence, and cell survival. The latent state typically occurs only in neurons, and may involve the attenuation of immediate early (IE) gene expression, and thus the lack of later viral gene expression. The IE protein ICP0 has been shown to facilitate the transition from the latent to the lytic state, thus leading to reaction episodes that are typical of herpesviruses. We have been investigating the behavior of viruses that do not express any of the five IE proteins upon cellular infection. While the viral genomes are transcriptionally quiescent and cytopathic effects are not seen, they can be rendered transcriptionally active by supplying ICP0 in trans. Thus this system has some of the key features associated with HSV latency, but is also more amenable to biochemical and molecular study. We have found that quiescent genomes are largely repressed and exist in multiple states that differ with respect to nucleosome packaging, histone acetylation and methylation, and heterochromatin formation. The result is a stochastic mix of epigenetic states that differ with respect to the expressibility of the genome. We study the ability of viral activator proteins to overcome these repressive states and their mechanisms of action.

Virus-cell interactions affecting HSV gene expression:  In its productive life cycle, the genes of HSV are expressed in a sequential manner, with those controlling subsequent gene expression produced very early in infection. One of these, ICP4, is required for productive virus infection because it activates the expression of the remaining 80 or so early and late genes. ICP4 activates early and late genes by different mechanisms involving different interaction with TFIID, mediator, and other cellular transcription factors. To study these mechanisms, we examine the association of ICP4 and cellular transcription complexes on HSV promoters during infection, the regions of ICP4 that are important for these interactions are determined, and subsequently the effects of these interactions on the transcription and hence expression of different classes of HSV genes is determined. In addition, we have discovered that there are regions of ICP4 that are not required for productive viral growth in non-neuronal cells, but are absolutely required for function in neurons of the trigeminal ganglia, the site where HSV establishes latency. The basis for this requirement is current under study.

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Frances Sivrich, Research Technician