The initiation of the herpes simplex virus lytic replication cycle depends upon the coordinated expression of the viral (IE) immediate early genes. These genes are controlled by a complex multiprotein enhancer assembly that consists of viral and cellular components. Studies of the various components, protein interactions, viral and cellular functions provides both a model for cellular transcriptional regulation as well as insights into the mechanisms utilized by the virus. The focus is the identification and characterization of the critical components of this regulatory pathway. The mammalian coactivator HCF-1 is one of the more complex factors involved in both the assembly of the enhancer complex and the activation of the IE genes. Studies focus upon both functions during the viral lytic cycle as well as in normal cellular processes. The importance of both is underscored by the complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Recent studies have determined that HCF-1 functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon infection. Additionally, HCF-1 modulate chromatin during HSV-1 DNA replication indicating that the protein plays critical roles throughout the viral lytic replication cycle. In 2013, additional HCF-1 associated histone modulatory complexes and components were identified that are critical elements of the viral IE gene regulatory paradigm. Small molecule inhibitors of these components were identified that block viral IE gene expression upon infection in cell culture and in vivo during primary infection.

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Alfonso-Dunn, Roberto; Turner, Anne-Marie W; Jean Beltran, Pierre M et al. (2017) Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency. Cell Host Microbe 21:507-517.e5
Kristie, Thomas M (2016) Chromatin Modulation of Herpesvirus Lytic Gene Expression: Managing Nucleosome Density and Heterochromatic Histone Modifications. MBio 7:e00098-16
Kristie, Thomas M (2015) Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies. Virology 479-480:555-61
Arbuckle, Jesse H; Kristie, Thomas M (2014) Epigenetic repression of herpes simplex virus infection by the nucleosome remodeler CHD3. MBio 5:e01027-13
Hill, James M; Quenelle, Debra C; Cardin, Rhonda D et al. (2014) Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes. Sci Transl Med 6:265ra169
Vogel, Jodi L; Kristie, Thomas M (2013) The dynamics of HCF-1 modulation of herpes simplex virus chromatin during initiation of infection. Viruses 5:1272-91
Liang, Yu; Vogel, Jodi L; Arbuckle, Jesse H et al. (2013) Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med 5:167ra5
Liang, Yu; Quenelle, Debra; Vogel, Jodi L et al. (2013) A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. MBio 4:e00558-12
Knipe, David M; Lieberman, Paul M; Jung, Jae U et al. (2013) Snapshots: chromatin control of viral infection. Virology 435:141-56
Kristie, Thomas M (2012) The rise of epigenetic targets for the development of novel antivirals. Expert Rev Anti Infect Ther 10:1359-61

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