Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, which is the infectious agent of two diseases, causing varicella (chickenpox) during primary infection and zoster (shingles) after reactivation from latency. A VZV vaccine is now in widespread use in children and may also be used in older adults in order to prevent zoster. In these contexts, it is essential for us to be able to understand the mechanisms of replication and virulence of this important human virus. During the past funding period we have identified the viral and cellular factors required for expression from a viral glycoprotein promoter and in doing so, have formulated a model for the mechanism of transactivation by the viral IE62 major transactivator. We have also assessed the roles of two other essential viral proteins (ORF 29 and ORF 63 proteins) in the regulation of VZV transcription. In this proposal we will refine our model of IE62 activation of the VZV gI promoter and examine the interaction of this protein with ubiquitous cellular transcription factors. We will expand our work on VZV transcription into questions regarding latent gene expression using a novel VZV lytic bidirectional promoter which functions unidirectionally in latency. Finally, we will examine the nature and the function of the interaction, identified during the last funding period, between the VZV IE62 and ORF 63 proteins and determine the function of the latter protein in VZV gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
2R21AI018449-20
Application #
6543023
Study Section
Virology Study Section (VR)
Program Officer
Beisel, Christopher E
Project Start
2002-07-15
Project End
2004-06-30
Budget Start
2002-07-15
Budget End
2004-06-30
Support Year
20
Fiscal Year
2002
Total Cost
$303,835
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Khalil, Mohamed I; Che, Xibing; Sung, Phillip et al. (2016) Mutational analysis of varicella-zoster virus (VZV) immediate early protein (IE62) subdomains and their importance in viral replication. Virology 492:82-91
Khalil, Mohamed I; Sommer, Marvin H; Hay, John et al. (2015) Varicella-zoster virus (VZV) origin of DNA replication oriS influences origin-dependent DNA replication and flanking gene transcription. Virology 481:179-86
Khalil, Mohamed I; Ruyechan, William T; Hay, John et al. (2015) Differential effects of Sp cellular transcription factors on viral promoter activation by varicella-zoster virus (VZV) IE62 protein. Virology 485:47-57
Khalil, Mohamed I; Sommer, Marvin; Arvin, Ann et al. (2014) Cellular transcription factor YY1 mediates the varicella-zoster virus (VZV) IE62 transcriptional activation. Virology 449:244-53
Khalil, Mohamed I; Sommer, Marvin; Arvin, Ann et al. (2013) Regulation of the varicella-zoster virus ORF3 promoter by cellular and viral factors. Virology 440:171-81
Khalil, Mohamed I; Robinson, Makeda; Sommer, Marvin et al. (2012) An Sp1/Sp3 site in the downstream region of varicella-zoster virus (VZV) oriS influences origin-dependent DNA replication and flanking gene transcription and is important for VZV replication in vitro and in human skin. J Virol 86:13070-80
Khalil, Mohamed I; Arvin, Ann; Jones, Jeremy et al. (2011) A sequence within the varicella-zoster virus (VZV) OriS is a negative regulator of DNA replication and is bound by a protein complex containing the VZV ORF29 protein. J Virol 85:12188-200
White, Kris; Peng, Hua; Hay, John et al. (2010) Role of the IE62 consensus binding site in transactivation by the varicella-zoster virus IE62 protein. J Virol 84:3767-79
Ruyechan, William T (2010) Roles of cellular transcription factors in VZV replication. Curr Top Microbiol Immunol 342:43-65
Yamamoto, Shinobu; Eletsky, Alexander; Szyperski, Thomas et al. (2009) Analysis of the varicella-zoster virus IE62 N-terminal acidic transactivating domain and its interaction with the human mediator complex. J Virol 83:6300-5