Neal A. DeLuca, PhD

The pathogenic and cytotoxic effects of viruses are largely due to the expression of viral gene products. The hallmark of herpes simplex virus gene expression is the sequential and coordinately regulated expression of the approximately 80 viral genes. Two viral proteins, VP16 and ICP4, function to activate transcription of the five immediate early genes, and the remainder of the HSV genome, respectively. ICP4 is a large and structurally complex molecule. We study the mechanisms by which the major regulatory protein of HSV, ICP4, affects the pol II transcriptional apparatus of the cell resulting in the regulation of HSV genes.

In addition to the modification of polII transcription by ICP4, many other cellular nuclear processes are modified by viral gene products to support productive infection.  Many of these processes function on the viral genome.  The viral genome is the only component of the virus present throughout its productive life cycle. We have developed approaches to determine in a nonbiased way, the viral and cellular proteins that associate with the genome throughout infection, from the initial sensing of the genome to its packaging, and to image these genomes relative to cellular structures and proteins.

HSV gene expression during lytic infection is contrasted by the ability to establish latency in PNS neurons. During latency, viral lytic gene expression does not occur, and the genome persists as an episomal element packaged in chromatin. The use of mutants deficient in subsets of the IE proteins provides the means to examine viral gene expression and genome persistence in the absence of lytic gene expression in tissue culture. Mutants that do not express any of the five IE proteins establish a long-term relationship with the cell. Gene expression from the persisting genomes is repressed by repressive chromatin, and interferon signaling is induced. Both processes can be reversed by the addition of ICP0. We study the interplay between genome repression, activation, and the cellular antiviral response.