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Functions of the immediate early 2 proteins in human cytomegalovirus infection : a study of immediate early 2 mutants


This dissertation contains four divisions represented in three chapters. The first chapter introduces the UL122 gene of human cytomegalovirus (HCMV) and its gene products : IE2 86, IE2 60 and IE2 40. Chapter 1 then goes on to describe the functions of the UL122 gene products. IE2 86 is an essential gene for HCMV infection expressed at immediate early times, which plays a role in its own autorepression as well as in the transactivation of other viral early and late genes. Some evidence has also implicated that IE2 86 played a role in cell cycle arrest during HCMV infection. IE2 60 and IE2 40 are expressed at late times of infection, and though non-essential, are known to play an important role in the expression of the essential UL84 protein. In the second chapter, we describe a mutation in the UL122 gene in which the amino acid at position 548 has been mutated from glutamine to arginine. Previous work on this mutant demonstrated its apparent inability to halt the cell cycle. However, our characterization in which the mutant virus was able to be grown in an IE2-complementing cell line, demonstrated that while it maintained its ability to halt the cell cycle, its expression of IE2 60, IE2 40, UL83, UL84, and UL99 was greatly reduced. A microarray analysis of this mutant further revealed increases in the transcription of US8-9 and US29-32; genes heretofore not know to be regulated by IE2 86. In addition, a microRNA found within the US29 gene known as miR-US33as was also shown to be upregulated in Q548R IE2 HCMV infection. A recombinant virus in which the degradation domain-containing FKBP protein was attached to the C-terminus of IE2 was made and lent further support to the notion that the levels of IE2 40 influence the levels of UL84. The last chapter discusses the link between IE2 86, IE2 60 and IE2 40 expression and their possible roles in UL84 and UL83 expression and suggests ways in which the relationships between these proteins can continue to be investigated

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