Regulation of viral and cellular gene expression in cells infected with herpes simplex virus

Abstract

<p>When herpes simplex virus (HSV) infects a cell, viral genes are expressed to high levels, while cellular gene expression is dramatically inhibited. The major goal of the work described in this thesis was to understand the molecular basis for differential expression of viral and cellular genes in HSV infected cells. A two part-approach was taken to examine this problem. First, I compared the expression of virally-transduced and endogenous β-globin genes in HSV infected cells. These experiments were prompted by previous work which demonstrated that an HSV transduced rabbit β-globin gene isefficiently expressed in infected Vero cells, a result that was in apparent conflict with previous experiments demonstrating that HSV infection inhibits the expression of the mouse β-globin gene resident in mouse erythroleukemia cells. This approach demonstrated that HSV products inhibit the expression of an endogenous β-globin gene while transactivating the expression of a virally transduced β-globin gene. These results illustrate that the selective inhibition of cellular gene expression plays an important role in the preferential expression of genes associated with the viral genome. Therefore, the second approach involved a detailed investigation of the herpes simplex virus vhs gene product, one of the viral functions that inhibits cellular gene expression. I have confirmed that the vhs effect requires the HSV UL41 open reading frame. in addition, I identified the vhs proteni as a 58kDa phosphoprotein that is packaged into virions. Using several approaches I demonstrated that the vhs protein interacts with the HSV transcription factor VP16. In addition, I have data which suggests this interaction downregulates the vhs function and that this downregulation might play a key role in the preferential expression of viral genes in the HSV infected cell.</p>