Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects the majority of the world's population. Although HCMV infection is usually sub-clinical in healthy individuals it can be a devastating disease in immunocompromised individuals such as neonates, transplant recipients, and AIDS patients. Our research program is focused on elucidating the molecular mechanisms that regulate HCMV replication and pathogenesis. Specifically, our research program is focused on determining what role tegument proteins play in regulating viral replication. Tegument proteins are packaged within virus particles and delivered to the host cell immediately after infection and can function prior to transcription from the viral genome. Using HCMV deletion mutants we have demonstrated that the UL82 and UL69 tegument proteins play critical roles in HCMV replication. UL82 and UL69 are similar in many respects including their ability to regulate viral gene expression, their ability to modulate the host cell cycle and most importantly they are both required for efficient viral replication. However, the mechanism by which these proteins regulate HCMV replication has not been elucidated. This proposal is designed to test the hypothesis that UL82 and UL69's ability to regulate viral gene expression is required for efficient virus replication. By utilizing UL82 and UL69 recombinant viruses and a number of genetic and biochemical approaches we will identify the critical functions associated with UL82 and UL69 and address the following specific aims: 1) elucidate the mechanism by whichpp71 regulates HCMV immediate early gene expression and HCMV replication;2) elucidate the mechanism by which ppUL69 regulates HCMV late gene expression and HCMV replication;and 3) identify and characterize cellular and/or viral proteins that interact functionally with pp71 or ppUL69. By understanding the function of these tegument proteins and elucidating the mechanism by which they regulate HCMV replication we may be able to identify novel approaches or therapeutics to help combat HCMV infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Beisel, Christopher E
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Phillips, Stacia L; Bresnahan, Wade A (2012) The human cytomegalovirus (HCMV) tegument protein UL94 is essential for secondary envelopment of HCMV virions. J Virol 86:2523-32
Phillips, Stacia L; Cygnar, Daniel; Thomas, Alexandra et al. (2012) Interaction between the human cytomegalovirus tegument proteins UL94 and UL99 is essential for virus replication. J Virol 86:9995-10005
Cygnar, Daniel; Hagemeier, Stacy; Kronemann, Daniel et al. (2012) The cellular protein SPT6 is required for efficient replication of human cytomegalovirus. J Virol 86:2011-20
Phillips, Stacia L; Bresnahan, Wade A (2011) Identification of binary interactions between human cytomegalovirus virion proteins. J Virol 85:440-7
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Kronemann, Daniel; Hagemeier, Stacy R; Cygnar, Dan et al. (2010) Binding of the human cytomegalovirus (HCMV) tegument protein UL69 to UAP56/URH49 is not required for efficient replication of HCMV. J Virol 84:9649-54
DeFilippis, Victor R; Sali, Tina; Alvarado, David et al. (2010) Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B. J Virol 84:8913-25
Cantrell, Stacy R; Bresnahan, Wade A (2006) Human cytomegalovirus (HCMV) UL82 gene product (pp71) relieves hDaxx-mediated repression of HCMV replication. J Virol 80:6188-91